We introduce a physiology-based mathematical model of sleep-wake cycles, suggesting a novel mechanism of homeostatic regulation of sleep. In this model, the homeostatic process is determined by the neuropeptide hypocretin/ orexin, which is a cotransmitter of the lateral hypothalamus. Hypocretin/ orexin neurons are silent during sleep and active during wakefulness. Firing of these neurons is sustained by reciprocal excitatory synaptic connections with local glutamate interneurons. This feedback loop has been simulated with a minimal but physiologically plausible model. It includes 2 simplified Hodgkin-Huxley type neurons that are connected via glutamate synapses, one of which additionally contains hypocretin/orexin as the functionally relevant cotransmitter. During the active state (wakefulness), the synaptic efficacy of hypocretin/orexin declines as a result of the ongoing firing. It recovers during the silent (sleep) state. We demonstrate that these homeostatic changes can account for typical alterations of sleep-wake transitions, for example, introduced by napping, sleep deprivation, or alarm clock. In combination with a circadian input, the model mimics the transitions between silent and firing states in agreement with sleep-wake cycles. These simulation results support the concept of state-dependent alterations of hypocretin/orexin effects as an important homeostatic process in sleep-wake regulation, although additional mechanisms can be involved.
Achermann P. ( 2004) The two-process model of sleep regulation revisited . Aviat Space Environ Med75(3):A37-A43.
2.
Albrecht U. ( 2002) Invited review: regulation of mammalian circadian clock genes. J Appl Physiol92:1348-1355.
3.
Basheer R., Strecker RE, Thakkar MM, and McCarley RW ( 2004) Adenosine and sleep-wake regulation. Prog Neurobiol73(6):379-396.
4.
Bazhenov M., Timofeev I., Steriade M., and Sejnowski TJ ( 2002) Model of thalamocortical slow-wave sleep oscillations and transitions to activated states. J Neurosci22:8691-8704.
5.
Best J., Diniz Behn CG, Poe GR, and Booth V. ( 2007) Neuronal models for sleep-wake regulation and synaptic reorganization in the sleeping hippocampus. J Biol Rhythms22(3):220-232.
6.
Borbély AA ( 1982) A two process model of sleep regulation. Hum Neurobiol1:195-204.
7.
Borbély AA and Achermann P. ( 1999) Sleep homeostasis and models of sleep regulation . J Biol Rhythms14:557-568.
8.
Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T., Lee C., Richardson JA, Williams SC, Xiong Y., Kisanuki Y., et al. (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell98(4):437-451.
9.
Chou TC ( 2003) A bistable model of sleep-wake regulation. In Regulation of Wake-Sleep Timing: Circadian Rhythms and Bistability of Sleep-Wake States, pp 82-99, Cambridge, MA, Harvard University.
10.
Daan S., Beersma DG, and Borbély AA (1984) Timing of human sleep: recovery process gated by a circadian pacemaker. Am J Physiol246:R161-R178.
11.
Deadwyler SA, Porrino L., Siegel JM, and Hampson RE ( 2007) Systemic and nasal delivery of orexin-A (hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci27(52):14239-14247.
12.
Diniz Behn CG, Brown EN, Scammell TE, and Kopell NJ ( 2007) Mathematical model of network dynamics governing mouse sleep-wake behavior. J Neurophysiol97(6):3828-3840.
13.
de Lecea L., Kilduff TS, Peyron C., Gao X., Foye PE, Danielson PE, Fukuhara C., Battenberg EL, Gautvik VT, Bartlett FS 2nd, et al. (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA95:322-327.
14.
Diniz Behn CG, Kopell N., Brown EN, Mochizuki T., and Scammell TE ( 2008) Delayed orexin signaling consolidates wakefulness and sleep: physiology and modeling. J Neurophysiol99:3090-3103.
15.
Esser SK, Hill SL, and Tononi G. ( 2007) Sleep homeostasis and cortical synchronization: I. Modeling the effects of synaptic strength on sleep slow waves. Sleep30:1617-1630.
16.
Finke C., Vollmer J., Postnova S., and Braun HA ( 2008) Propagation effects of current and conductance noise in a model neuron with subthreshold oscillations. Math Biosci214(1-2):109-121.
17.
Fujiki N., Yoshida Y., Ripley B., Honda K., Mignot E., and Nishino S. ( 2001) Changes in CSF hypocretin-1 (orexin A) levels in rats across 24 hours and in response to food deprivation. Neuroreport12(5):993-997.
18.
Gerashchenko D., Kohls MD, Greco M., Waleh NS, Salin-Pascual R., Kilduff TS, Lappi DA, and Shiromani PJ ( 2001) Hypocretin-2-saporin lesions of the lateral hypothalamus produce narcoleptic-like sleep behavior in the rat. J Neurosci21(18):7273-7283.
19.
Herzog ED, Takahashi JS, and Block GD ( 1998) Clock controls circadian period in isolated suprachiasmatic nucleus neurons. Nature Neurosci1:708-713.
20.
Hill S. and Tononi G. ( 2005) Modeling sleep and wakefulness in the thalamocortical system. J Neurophysiol93:1671-1698.
21.
Honma S., Shirakawa T., Katsuno Y., Namihira M., and Honma K. ( 1998) Circadian periods of single suprachiasmatic neurons in rats. Neurosci Lett250:157-160.
22.
Ida T., Nakahara K., Katayama T., Murakami N., and Nakazato M. ( 1999) Effect of lateral cerebroventricular injection of the appetite-stimulating neuropeptide, orexin and neuropeptide Y, on the various behavioral activities of rats. Brain Res821:526-529.
23.
Kandel ER, Scwartz JH, and Jessell TM ( 1991) Arousal, emotion, and behavioral homeostasis. In Principles of Neural Science, Kandel ER, Scwartz JH, and Jessell TM, eds, pp 869-1014, New York, McGraw-Hill.
24.
Landolt HP ( 2008) Sleep homeostasis: a role for adenosine in humans ? Biochem Pharmacol75(11):2070-2079.
25.
Lee MG, Hassani OK, and Jones BE ( 2005) Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J Neurosci25(28):6716-6720.
26.
Li Y., Gao XB, Sakurai T., and van den Pol AN ( 2002) Hypocretin/orexin excites hypocretin neurons via a local glutamate neuron-A potential mechanism for orchestrating the hypothalamic arousal system. Neuron36:1169-1181.
27.
Lin L., Faraco J., Li R., Kadotani H., Rogers W., Lin X., Qiu X., de Jong PJ, Nishino S., and Mignot E. ( 1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell98(3):365-376.
28.
Mileykovskiy BY, Kiyashchenko LI, and Siegel JM ( 2005) Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron46:787-798.
29.
Mistlberger RE ( 2005) Circadian regulation of sleep in mammals: role of the suprachiasmatic nucleus. Brain Res Rev49:429-454.
30.
Mochizuki T., Crocker A., McCormack S., Yanagisawa M., Sakurai T., and Scammell TE ( 2004) Behavioral state instability in orexin knock-out mice . J Neurosci24(28): 6291-6300.
31.
Moore RY ( 2007) Suprachiasmatic nucleus in sleep-wake regulation . Sleep Med8(3):27-33.
32.
Nishino S., Ripley B., Overeem S., Lammers GJ, and Mignot E. ( 2000) Hypocretin (orexin) deficiency in human narcolepsy . Lancet355(9197):39-40.
33.
Peyron C., Tighe DK, van den Pol AN, de Lecea L., Heller HC, Sutcliffe JG, and Kilduff TS ( 1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci18(23):9996-10015.
34.
Phillips AJK and Robinson PA ( 2007) A quantitative model of sleep-wake dynamics based on the physiology of the brainstem ascending arousal system. J Biol Rhythms22:167-179.
35.
Rao Y., Liu ZW, Borok E., Rabenstein RL, Shanabrough M., Lu M., Picciotto MR, Horvath TL, and Gao XB ( 2007) Prolonged wakefulness induces experience-dependent synaptic plasticity in mouse hypocretin/orexin neurons. J Clin Invest117(12):4022-4033.
36.
Sakurai T. ( 2007) The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci8:171-181.
37.
Sakurai T., Amemiya A., Ishii M., Matsuzaki I., Chemelli RM, Tanaka H., Williams SC, Richardson JA, Kozlowski GP, Wilson S., et al. (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G-protein coupled receptors that regulate feeding behavior. Cell92:573-585.
38.
Salomon RM, Ripley B., Kennedy JS, Johnson B., Schmidt D., Zeitzer JM, Nishino S., and Mignot E. ( 2003) Diurnal variation of cerebrospinal fluid hypocretin-1 (Orexin-A) levels in control and depressed subjects. Biol Psychiatry54(2):96-104.
39.
Saper CB, Scammell TE, and Lu J. ( 2005) Hypothalamic regulation of sleep and circadian rhythms . Nature437(27):1257-1263.
40.
Sherin JE, Shiromani PJ, McCarley RW, and Saper CB ( 1996) Activation of ventrolateral preoptic neurons during sleep . Science271:216-219.
41.
Stenberg D., Litonius E., Halldner L., Johansson B., Fredholm BB, and Porkka-Heiskanen T. (2003) Sleep and its homeostatic regulation in mice lacking the adenosine A1 receptor. J Sleep Res12(4):283-290.
42.
Sutcliffe JG and de Lecea L. ( 2002) The hypocretins: setting the arousal threshold . Nat Rev Neurosci3(5):339-49.
43.
Tamakawa Y., Karashima A., Koyama Y., Katayama N., and Nakao M. ( 2007) A quartet neural system model orchestrating sleep and wakefulness mechanisms. J Neurophysiol95:2055-2069.
44.
Tessone CJ, Mirasso CR, Toral R., and Gunton JD ( 2006) Diversity-induced resonance. Phys Rev Lett97(19): 194101-194105.
45.
Thannickal TC, Moore RY, Nienhuis R., Ramanathan L., Gulyani S., Aldrich M., Cornford M., and Siegel JM ( 2000) Reduced number of hypocretin neurons in human narcolepsy . Neuron27:469-474.
46.
Tononi G. and Cirelli C. ( 2006) Sleep function and synaptic homeostasis. Sleep Med Rev10(1):49-62.
47.
Winsky-Sommerer R., Yamanaka A., Diano S., Borok E., Roberts AJ, Sakurai T., Kilduff TS, Horvath TL, and de Lecea L. ( 2004) Interaction between the corticotropinreleasing factor system and hypocretins (orexins): a novel circuit mediating stress response . J Neurosci24:11439-11448.
48.
Yoshida K., McCormack S., Espana RA, Crocker A., and Scammell TE ( 2006) Afferents to the orexin neurons of the rat brain . J Comp Neurol494:845-861.
49.
Zeitzer JM, Buckmaster CL, Parker KJ, Hauck CM, Lyons DM, and Mignot E. ( 2003) Circadian and homeostatic regulation of hypocretin in a primate model: implications for the consolidation of wakefulness. J Neurosci23(8):3555-3560.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
