Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Circuit-based interrogation of sleep control

Abstract

Sleep is a fundamental biological process observed widely in the animal kingdom, but the neural circuits generating sleep remain poorly understood. Understanding the brain mechanisms controlling sleep requires the identification of key neurons in the control circuits and mapping of their synaptic connections. Technical innovations over the past decade have greatly facilitated dissection of the sleep circuits. This has set the stage for understanding how a variety of environmental and physiological factors influence sleep. The ability to initiate and terminate sleep on command will also help us to elucidate its functions within and beyond the brain.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Sleep in humans and mice.
Figure 2: Methods for neuronal manipulations.
Figure 3: Methods for measuring neural activity.
Figure 4: Circuit diagram for forebrain sleep-promoting mechanisms.
Figure 5: Brainstem circuits controlling REM and NREM sleep.

References

  1. Shein-Idelson, M., Ondracek, J. M., Liaw, H.-P., Reiter, S. & Laurent, G. Slow waves, sharp waves, ripples, and REM in sleeping dragons. Science 352, 590–595 (2016).This study reports for the first time the existence of REM- and NREM-like sleep stages in a reptile, the Australian dragon Pogona vitticeps . Comparative analysis might shed light on the common circuitry underlying ultradian rhythms in reptiles and mammals.

    ADS  CAS  PubMed  Article  Google Scholar 

  2. Aserinsky, E. & Kleitman, N. Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science 118, 273–274 (1953)

    ADS  CAS  Article  PubMed  Google Scholar 

  3. Zepelin, H., Siegel, J. M. & Tobler, I. in Principles and practice of sleep medicine 4, 91–100 (eds Kryger, M. H. et al., Elsevier Saunders, 2005)

    Article  Google Scholar 

  4. Moruzzi, G. & Magoun, H. W. Brain stem reticular formation and activation of the EEG. Electroencephalogr. Clin. Neurophysiol. 1, 455–473 (1949)

    CAS  PubMed  Article  Google Scholar 

  5. Brown, R. E., Basheer, R., McKenna, J. T., Strecker, R. E. & McCarley, R. W. Control of sleep and wakefulness. Physiol. Rev. 92, 1087–1187 (2012)

    CAS  PubMed  Article  Google Scholar 

  6. Saper, C. B., Fuller, P. M., Pedersen, N. P., Lu, J. & Scammell, T. E. Sleep state switching. Neuron 68, 1023–1042 (2010)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Deisseroth, K. Optogenetics. Nat. Methods 8, 26–29 (2011)

    CAS  Article  PubMed  Google Scholar 

  8. Armbruster, B. N., Li, X., Pausch, M. H., Herlitze, S. & Roth, B. L. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc. Natl Acad. Sci. USA 104, 5163–5168 (2007)

    ADS  Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tian, L., Hires, S. A. & Looger, L. L. Imaging neuronal activity with genetically encoded calcium indicators. Cold Spring Harb. Protoc. 2012, 647–656 (2012)

    PubMed  Article  Google Scholar 

  10. Oh, S. W. et al. A mesoscale connectome of the mouse brain. Nature 508, 207–214 (2014)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Osakada, F. & Callaway, E. M. Design and generation of recombinant rabies virus vectors. Nat. Protocols 8, 1583–1601 (2013)

    Article  CAS  PubMed  Google Scholar 

  12. Rihel, J. & Schier, A. F. Sites of action of sleep and wake drugs: insights from model organisms. Curr. Opin. Neurobiol. 23, 831–840 (2013)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Sehgal, A. & Mignot, E. Genetics of sleep and sleep disorders. Cell 146, 194–207 (2011)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 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)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Trojanowski, N. F. & Raizen, D. M. Call it worm sleep. Trends Neurosci. 39, 54–62 (2016)

    CAS  PubMed  Article  Google Scholar 

  16. Andretic, R., Franken, P. & Tafti, M. Genetics of sleep. Annu. Rev. Genet. 42, 361–388 (2008)

    CAS  PubMed  Article  Google Scholar 

  17. Von Economo, C. Sleep as a problem of localization. J. Nerv. Ment. Dis. 71, 249–259 (1930)

    Article  Google Scholar 

  18. Nauta, W. J. Hypothalamic regulation of sleep in rats; an experimental study. J. Neurophysiol. 9, 285–316 (1946)

    CAS  PubMed  Article  Google Scholar 

  19. McGinty, D. J. & Sterman, M. B. Sleep suppression after basal forebrain lesions in the cat. Science 160, 1253–1255 (1968)

    ADS  CAS  PubMed  Article  Google Scholar 

  20. Sallanon, M. et al. Long-lasting insomnia induced by preoptic neuron lesions and its transient reversal by muscimol injection into the posterior hypothalamus in the cat. Neuroscience 32, 669–683 (1989)

    CAS  PubMed  Article  Google Scholar 

  21. Lin, J.-S., Sakai, K., Vanni-Mercier, G. & Jouvet, M. A critical role of the posterior hypothalamus in the mechanisms of wakefulness determined by microinjection of muscimol in freely moving cats. Brain Res. 479, 225–240 (1989)

    CAS  PubMed  Article  Google Scholar 

  22. Sherin, J. E., Shiromani, P. J., McCarley, R. W. & Saper, C. B. Activation of ventrolateral preoptic neurons during sleep. Science 271, 216–219 (1996)

    ADS  CAS  Article  PubMed  Google Scholar 

  23. Gong, H. et al. Activation of c-fos in GABAergic neurones in the preoptic area during sleep and in response to sleep deprivation. J. Physiol. (Lond.) 556, 935–946 (2004)

    CAS  Article  Google Scholar 

  24. Lu, J., Greco, M. A., Shiromani, P. & Saper, C. B. Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep. J. Neurosci. 20, 3830–3842 (2000)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Zhang, Z. et al. Neuronal ensembles sufficient for recovery sleep and the sedative actions of α2 adrenergic agonists. Nat. Neurosci. 18, 553–561 (2015).This study used a pharmacogenetic approach to activate POA neurons that expressed c-Fos following sustained sleep to show that they indeed promote sleep.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Sherin, J. E., Elmquist, J. K., Torrealba, F. & Saper, C. B. Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J. Neurosci. 18, 4705–4721 (1998)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Steininger, T. L., Gong, H., McGinty, D. & Szymusiak, R. Subregional organization of preoptic area/anterior hypothalamic projections to arousal-related monoaminergic cell groups. J. Comp. Neurol. 429, 638–653 (2001)

    CAS  PubMed  Article  Google Scholar 

  28. Yoshida, K., McCormack, S., España, R. A., Crocker, A. & Scammell, T. E. Afferents to the orexin neurons of the rat brain. J. Comp. Neurol. 494, 845–861 (2006)

    PubMed  PubMed Central  Article  Google Scholar 

  29. Adamantidis, A. R., Zhang, F., Aravanis, A. M., Deisseroth, K. & de Lecea, L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 450, 420–424 (2007).This study was the first to apply optogenetics to investigate circuits involved in sleep–wake regulation and it provided causal evidence that orexin neurons promote wakefulness.

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Lu, J., Jhou, T. C. & Saper, C. B. Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter. J. Neurosci. 26, 193–202 (2006)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Fuller, P. M., Sherman, D., Pedersen, N. P., Saper, C. B. & Lu, J. Reassessment of the structural basis of the ascending arousal system. J. Comp. Neurol. 519, 933–956 (2011)

    PubMed  PubMed Central  Article  Google Scholar 

  32. Gaus, S. E., Strecker, R. E., Tate, B. A., Parker, R. A. & Saper, C. B. Ventrolateral preoptic nucleus contains sleep-active, galaninergic neurons in multiple mammalian species. Neuroscience 115, 285–294 (2002)

    CAS  Article  PubMed  Google Scholar 

  33. Steininger, T. L., Alam, M. N., Gong, H., Szymusiak, R. & McGinty, D. Sleep-waking discharge of neurons in the posterior lateral hypothalamus of the albino rat. Brain Res. 840, 138–147 (1999)

    CAS  PubMed  Article  Google Scholar 

  34. Nitz, D. & Siegel, J. M. GABA release in the locus coeruleus as a function of sleep/wake state. Neuroscience 78, 795–801 (1997)

    CAS  PubMed  Article  Google Scholar 

  35. Nitz, D. & Siegel, J. GABA release in the dorsal raphe nucleus: role in the control of REM sleep. Am. J. Physiol. 273, R451–R455 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Hobson, J. A., McCarley, R. W. & Wyzinski, P. W. Sleep cycle oscillation: reciprocal discharge by two brainstem neuronal groups. Science 189, 55–58 (1975)

    ADS  CAS  PubMed  Article  Google Scholar 

  37. Schönrock, B., Büsselberg, D. & Haas, H. L. Properties of tuberomammillary histamine neurones and their response to galanin. Agents Actions 33, 135–137 (1991)

    PubMed  Article  Google Scholar 

  38. Pieribone, V. A. et al. Galanin induces a hyperpolarization of norepinephrine-containing locus coeruleus neurons in the brainstem slice. Neuroscience 64, 861–874 (1995)

    CAS  PubMed  Article  Google Scholar 

  39. Chou, T. C. et al. Afferents to the ventrolateral preoptic nucleus. J. Neurosci. 22, 977–990 (2002)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Gallopin, T. et al. Identification of sleep-promoting neurons in vitro. Nature 404, 992–995 (2000)

    ADS  CAS  PubMed  Article  Google Scholar 

  41. Liu, Y.-W., Li, J. & Ye, J.-H. Histamine regulates activities of neurons in the ventrolateral preoptic nucleus. J. Physiol. (Lond.) 588, 4103–4116 (2010)

    CAS  Article  Google Scholar 

  42. Yu, X. et al. Wakefulness is governed by GABA and histamine cotransmission. Neuron 87, 164–178 (2015).This study demonstrated that histaminergic neurons in the TMN co-release histamine and GABA. Abolishing VGAT expression in histaminergic neurons increases wakefulness. Hence, the wake-promoting effect of histamine might be balanced by the co-release of GABA.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Greco, M.-A. et al. Opioidergic projections to sleep-active neurons in the ventrolateral preoptic nucleus. Brain Res. 1245, 96–107 (2008)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Varin, C. et al. Glucose induces slow-wave sleep by exciting the sleep-promoting neurons in the ventrolateral preoptic nucleus: a new link between sleep and metabolism. J. Neurosci. 35, 9900–9911 (2015).This study demonstrated that sleep-active neurons in the preoptic area are excited by glucose, which may provide a neuronal link between metabolism and sleep.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Yamanaka, A. et al. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38, 701–713 (2003)

    CAS  PubMed  Article  Google Scholar 

  46. Boulant, J. A. & Dean, J. B. Temperature receptors in the central nervous system. Annu. Rev. Physiol. 48, 639–654 (1986)

    CAS  PubMed  Article  Google Scholar 

  47. Alam, M. N., McGinty, D. & Szymusiak, R. Neuronal discharge of preoptic/anterior hypothalamic thermosensitive neurons: relation to NREM sleep. Am. J. Physiol. 269, R1240–R1249 (1995)

    CAS  PubMed  Google Scholar 

  48. Szymusiak, R., Alam, N., Steininger, T. L. & McGinty, D. Sleep-waking discharge patterns of ventrolateral preoptic/anterior hypothalamic neurons in rats. Brain Res. 803, 178–188 (1998)

    CAS  PubMed  Article  Google Scholar 

  49. Takahashi, K., Lin, J.-S. & Sakai, K. Characterization and mapping of sleep-waking specific neurons in the basal forebrain and preoptic hypothalamus in mice. Neuroscience 161, 269–292 (2009).A tour de force study recording hundreds of neurons in the preoptic area and basal forebrain during the sleep–wake cycle, demonstrating a staggering functional diversity among the neurons.

    CAS  Article  PubMed  Google Scholar 

  50. Modirrousta, M., Mainville, L. & Jones, B. E. GABAergic neurons with α2-adrenergic receptors in basal forebrain and preoptic area express c-Fos during sleep. Neuroscience 129, 803–810 (2004)

    CAS  PubMed  Article  Google Scholar 

  51. Wu, Z., Autry, A. E., Bergan, J. F., Watabe-Uchida, M. & Dulac, C. G. Galanin neurons in the medial preoptic area govern parental behaviour. Nature 509, 325–330 (2014)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Buzsaki, G. et al. Nucleus basalis and thalamic control of neocortical activity in the freely moving rat. J. Neurosci. 8, 4007–4026 (1988)

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. Hassani, O. K., Lee, M. G., Henny, P. & Jones, B. E. Discharge profiles of identified GABAergic in comparison to cholinergic and putative glutamatergic basal forebrain neurons across the sleep-wake cycle. J. Neurosci. 29, 11828–11840 (2009)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Szymusiak, R. & McGinty, D. Sleep-waking discharge of basal forebrain projection neurons in cats. Brain Res. Bull. 22, 423–430 (1989)

    CAS  PubMed  Article  Google Scholar 

  55. Lee, M. G., Hassani, O. K., Alonso, A. & Jones, B. E. Cholinergic basal forebrain neurons burst with theta during waking and paradoxical sleep. J. Neurosci. 25, 4365–4369 (2005).This study recorded for the first time from identified cholinergic basal forebrain neurons using the juxtacellular labelling technique. These neurons showed highest activity during waking and REM sleep, when hippocampal theta activity is high.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Han, Y. et al. Selective activation of cholinergic basal forebrain neurons induces immediate sleep-wake transitions. Curr. Biol. 24, 693–698 (2014)

    CAS  PubMed  Article  Google Scholar 

  57. Xu, M. et al. Basal forebrain circuit for sleep-wake control. Nat. Neurosci. 18, 1641–1647 (2015).Combining optogenetic activation, optrode recordings and in vitro physiology, this study thoroughly examined how the local interaction of different cell types in the basal forebrain underlies sleep–wake regulation.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Zaborszky, L. & Duque, A. Local synaptic connections of basal forebrain neurons. Behav. Brain Res. 115, 143–158 (2000)

    CAS  PubMed  Article  Google Scholar 

  59. Yang, C. et al. Cholinergic neurons excite cortically projecting basal forebrain GABAergic neurons. J. Neurosci. 34, 2832–2844 (2014)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Zant, J. C. et al. Cholinergic neurons in the basal forebrain promote wakefulness by actions on neighboring non-cholinergic neurons: an opto-dialysis study. J. Neurosci. 36, 2057–2067 (2016).This study used a novel opto-dialysis probe (combining optogenetic activation with microdyalisis) to demonstrate that local release of acethylcholine within the basal forebrain is crucial for cortical activation.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Hassani, O. K., Henny, P., Lee, M. G. & Jones, B. E. GABAergic neurons intermingled with orexin and MCH neurons in the lateral hypothalamus discharge maximally during sleep. Eur. J. Neurosci. 32, 448–457 (2010)

    PubMed  PubMed Central  Article  Google Scholar 

  62. Jego, S. et al. Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus. Nat. Neurosci. 16, 1637–1643 (2013).This study applied an optogenetic, closed-loop stimulation protocol to describe the role of hypothalamic MCH neurons in REM sleep maintenance in addition to induction.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Hassani, O. K., Lee, M. G. & Jones, B. E. Melanin-concentrating hormone neurons discharge in a reciprocal manner to orexin neurons across the sleep-wake cycle. Proc. Natl Acad. Sci. USA 106, 2418–2422 (2009)

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. Tsunematsu, T. et al. Optogenetic manipulation of activity and temporally controlled cell-specific ablation reveal a role for MCH neurons in sleep/wake regulation. J. Neurosci. 34, 6896–6909 (2014)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Konadhode, R. R. et al. Optogenetic stimulation of MCH neurons increases sleep. J. Neurosci. 33, 10257–10263 (2013)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Rao, Y. et al. Regulation of synaptic efficacy in hypocretin/orexin-containing neurons by melanin concentrating hormone in the lateral hypothalamus. J. Neurosci. 28, 9101–9110 (2008)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. Apergis-Schoute, J. et al. Optogenetic evidence for inhibitory signaling from orexin to MCH neurons via local microcircuits. J. Neurosci. 35, 5435–5441 (2015)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Jouvet, M. Recherches sur les structures nerveuses et les mécanismes responsables des différentes phases du sommeil physiologique. Arch. Ital. Biol. 100, 125–206 (1962)

    CAS  PubMed  Google Scholar 

  69. McCarley, R. W. & Hobson, J. A. Neuronal excitability modulation over the sleep cycle: a structural and mathematical model. Science 189, 58–60 (1975)

    ADS  CAS  PubMed  Article  Google Scholar 

  70. Clément, O., Sapin, E., Bérod, A., Fort, P. & Luppi, P.-H. Evidence that neurons of the sublaterodorsal tegmental nucleus triggering paradoxical (REM) sleep are glutamatergic. Sleep 34, 419–423 (2011)

    PubMed  PubMed Central  Article  Google Scholar 

  71. Hayashi, Y. et al. Cells of a common developmental origin regulate REM/non-REM sleep and wakefulness in mice. Science 350, 957–961 (2015).This study identified two sets of glutamatergic neurons in the pontine brainstem of a common developmental lineage that promote NREM sleep and wakefulness. The NREM-promoting neurons might suppress REM sleep by activating GABAergic vlPAG neurons.

    CAS  PubMed  Article  Google Scholar 

  72. Lu, J., Sherman, D., Devor, M. & Saper, C. B. A putative flip-flop switch for control of REM sleep. Nature 441, 589–594 (2006)

    ADS  CAS  PubMed  Article  Google Scholar 

  73. Sapin, E. et al. Localization of the brainstem GABAergic neurons controlling paradoxical (REM) sleep. PLoS One 4, e4272 (2009)

    ADS  PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. Weber, F. et al. Control of REM sleep by ventral medulla GABAergic neurons. Nature 526, 435–438 (2015).This study identified a brainstem circuit controlling the induction and maintenance of REM sleep using optogenetics, in vivo physiology and viral tracing techniques.

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Anaclet, C. et al. The GABAergic parafacial zone is a medullary slow wave sleep-promoting center. Nat. Neurosci. 17, 1217–1224 (2014).Identification of a novel group of sleep-promoting neurons in the rostral medulla.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Anaclet, C. et al. Identification and characterization of a sleep-active cell group in the rostral medullary brainstem. J. Neurosci. 32, 17970–17976 (2012)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. Boissard, R. et al. The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study. Eur. J. Neurosci. 16, 1959–1973 (2002)

    PubMed  Article  Google Scholar 

  78. George, R., Haslett, W. L. & Jenden, D. J. A cholinergic mechanism in the brainstem reticular formation: induction of paradoxical sleep. Int. J. Neuropharmacol. 3, 541–552 (1964)

    CAS  PubMed  Article  Google Scholar 

  79. Boucetta, S., Cissé, Y., Mainville, L., Morales, M. & Jones, B. E. Discharge profiles across the sleep-waking cycle of identified cholinergic, GABAergic, and glutamatergic neurons in the pontomesencephalic tegmentum of the rat. J. Neurosci. 34, 4708–4727 (2014)

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  80. Shouse, M. N. & Siegel, J. M. Pontine regulation of REM sleep components in cats: integrity of the pedunculopontine tegmentum (PPT) is important for phasic events but unnecessary for atonia during REM sleep. Brain Res. 571, 50–63 (1992)

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  81. Grace, K. P., Vanstone, L. E. & Horner, R. L. Endogenous cholinergic input to the pontine REM sleep generator is not required for REM sleep to occur. J. Neurosci. 34, 14198–14209 (2014)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Van Dort, C. J. et al. Optogenetic activation of cholinergic neurons in the PPT or LDT induces REM sleep. Proc. Natl Acad. Sci. USA 112, 584–589 (2015).The role of cholinergic brainstem neurons in the control of REM sleep has been intensively debated. This optogenetic study provided evidence that these neurons are involved in the induction rather than the maintenance of REM sleep.

    ADS  CAS  PubMed  Article  Google Scholar 

  83. Sakai, K. & Koyama, Y. Are there cholinergic and non-cholinergic paradoxical sleep-on neurones in the pons? Neuroreport 7, 2449–2453 (1996)

    CAS  PubMed  Article  Google Scholar 

  84. Maloney, K. J., Mainville, L. & Jones, B. E. Differential c-Fos expression in cholinergic, monoaminergic, and GABAergic cell groups of the pontomesencephalic tegmentum after paradoxical sleep deprivation and recovery. J. Neurosci. 19, 3057–3072 (1999)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. Cox, J., Pinto, L. & Dan, Y. Calcium imaging of sleep-wake related neuronal activity in the dorsal pons. Nat. Commun. 7, 10763 (2016)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. Krenzer, M. et al. Brainstem and spinal cord circuitry regulating REM sleep and muscle atonia. PLoS One 6, e24998 (2011)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. Schenkel, E. & Siegel, J. M. REM sleep without atonia after lesions of the medial medulla. Neurosci. Lett. 98, 159–165 (1989)

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  88. Magoun, H. W. & Rhines, R. An inhibitory mechanism in the bulbar reticular formation. J. Neurophysiol. 9, 165–171 (1946)

    CAS  PubMed  Article  Google Scholar 

  89. Arrigoni, E. & Saper, C. B. What optogenetic stimulation is telling us (and failing to tell us) about fast neurotransmitters and neuromodulators in brain circuits for wake-sleep regulation. Curr. Opin. Neurobiol. 29, 165–171 (2014)

    CAS  PubMed  Article  Google Scholar 

  90. Batini, C., Moruzzi, G., Palestini, M., Rossi, G. F. & Zanchetti, A. Persistent patterns of wakefulness in the pretrigeminal midpontine preparation. Science 128, 30–32 (1958)

    ADS  CAS  PubMed  Article  Google Scholar 

  91. Magnes, J., Moruzzi, G. & Pompeiano, O. Synchronization of the EEG produced by low-frequency electrical stimulation of the region of the solitary tract. Arch. Ital. Biol. 99, 33–67 (1961)

    Google Scholar 

  92. Eguchi, K. & Satoh, T. Characterization of the neurons in the region of solitary tract nucleus during sleep. Physiol. Behav. 24, 99–102 (1980)

    CAS  PubMed  Article  Google Scholar 

  93. Sastre, J. P., Buda, C., Kitahama, K. & Jouvet, M. Importance of the ventrolateral region of the periaqueductal gray and adjacent tegmentum in the control of paradoxical sleep as studied by muscimol microinjections in the cat. Neuroscience 74, 415–426 (1996)

    CAS  PubMed  Article  Google Scholar 

  94. Aston-Jones, G., Ennis, M., Pieribone, V. A., Nickell, W. T. & Shipley, M. T. The brain nucleus locus coeruleus: restricted afferent control of a broad efferent network. Science 234, 734–737 (1986)

    ADS  CAS  PubMed  Article  Google Scholar 

  95. Clément, O. et al. The inhibition of the dorsal paragigantocellular reticular nucleus induces waking and the activation of all adrenergic and noradrenergic neurons: a combined pharmacological and functional neuroanatomical study. PLoS One 9, e96851 (2014)

    ADS  PubMed  PubMed Central  Article  CAS  Google Scholar 

  96. Borbély, A. A. A two process model of sleep regulation. Hum. Neurobiol. 1, 195–204 (1982)

    PubMed  Google Scholar 

  97. Dijk, D. J., Brunner, D. P., Beersma, D. G. & Borbély, A. A. Electroencephalogram power density and slow wave sleep as a function of prior waking and circadian phase. Sleep 13, 430–440 (1990)

    CAS  PubMed  Article  Google Scholar 

  98. Franken, P., Chollet, D. & Tafti, M. The homeostatic regulation of sleep need is under genetic control. J. Neurosci. 21, 2610–2621 (2001)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Ishimori, K. True cause of sleep: a hypnogenic substance as evidenced in the brain of sleep-deprived animals. Tokyo Igakkai Zasshi 23, 429–457 (1909)

    Google Scholar 

  100. Legendre, R. & Pieron, H. Recherches sur le besoin de sommeil consécutif à une veille prolongée. Z. Allg. Physiol. 14, 235–262 (1913)

    Google Scholar 

  101. Porkka-Heiskanen, T. et al. Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science 276, 1265–1268 (1997)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. Porkka-Heiskanen, T., Strecker, R. E. & McCarley, R. W. Brain site-specificity of extracellular adenosine concentration changes during sleep deprivation and spontaneous sleep: an in vivo microdialysis study. Neuroscience 99, 507–517 (2000)

    CAS  PubMed  Article  Google Scholar 

  103. Kalinchuk, A. V., McCarley, R. W., Stenberg, D., Porkka-Heiskanen, T. & Basheer, R. The role of cholinergic basal forebrain neurons in adenosine-mediated homeostatic control of sleep: lessons from 192 IgG-saporin lesions. Neuroscience 157, 238–253 (2008)

    CAS  PubMed  Article  Google Scholar 

  104. Bjorness, T. E. et al. An adenosine-mediated glial-neuronal circuit for homeostatic sleep. J. Neurosci. 36, 3709–3721 (2016)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Halassa, M. M. et al. Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron 61, 213–219 (2009)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. Huang, Z.-L. et al. Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nat. Neurosci. 8, 858–859 (2005)

    CAS  PubMed  Article  Google Scholar 

  107. Urade, Y. et al. Sleep regulation in adenosine A2A receptor-deficient mice. Neurology 61 (Suppl 6), S94–S96 (2003)

    CAS  PubMed  Article  Google Scholar 

  108. Kumar, S. et al. Adenosine A2A receptors regulate the activity of sleep regulatory GABAergic neurons in the preoptic hypothalamus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305, R31–R41 (2013)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. Scammell, T. E. et al. An adenosine A2a agonist increases sleep and induces Fos in ventrolateral preoptic neurons. Neuroscience 107, 653–663 (2001)

    CAS  PubMed  Article  Google Scholar 

  110. Alam, M. A., Kumar, S., McGinty, D., Alam, M. N. & Szymusiak, R. Neuronal activity in the preoptic hypothalamus during sleep deprivation and recovery sleep. J. Neurophysiol. 111, 287–299 (2014)

    CAS  PubMed  Article  Google Scholar 

  111. Morairty, S., Rainnie, D., McCarley, R. & Greene, R. Disinhibition of ventrolateral preoptic area sleep-active neurons by adenosine: a new mechanism for sleep promotion. Neuroscience 123, 451–457 (2004)

    CAS  PubMed  Article  Google Scholar 

  112. Gallopin, T. et al. The endogenous somnogen adenosine excites a subset of sleep-promoting neurons via A2A receptors in the ventrolateral preoptic nucleus. Neuroscience 134, 1377–1390 (2005)

    CAS  PubMed  Article  Google Scholar 

  113. Arrigoni, E., Chamberlin, N. L., Saper, C. B. & McCarley, R. W. Adenosine inhibits basal forebrain cholinergic and noncholinergic neurons in vitro. Neuroscience 140, 403–413 (2006)

    CAS  PubMed  Article  Google Scholar 

  114. Liu, Z.-W. & Gao, X.-B. Adenosine inhibits activity of hypocretin/orexin neurons by the A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect. J. Neurophysiol. 97, 837–848 (2007)

    CAS  PubMed  Article  Google Scholar 

  115. Oishi, Y., Huang, Z.-L., Fredholm, B. B., Urade, Y. & Hayaishi, O. Adenosine in the tuberomammillary nucleus inhibits the histaminergic system via A1 receptors and promotes non-rapid eye movement sleep. Proc. Natl Acad. Sci. USA 105, 19992–19997 (2008)

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  116. Stenberg, D. et al. Sleep and its homeostatic regulation in mice lacking the adenosine A1 receptor. J. Sleep Res. 12, 283–290 (2003)

    ADS  PubMed  Article  Google Scholar 

  117. Bjorness, T. E., Kelly, C. L., Gao, T., Poffenberger, V. & Greene, R. W. Control and function of the homeostatic sleep response by adenosine A1 receptors. J. Neurosci. 29, 1267–1276 (2009)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. Porkka-Heiskanen, T. Sleep homeostasis. Curr. Opin. Neurobiol. 23, 799–805 (2013)

    CAS  PubMed  Article  Google Scholar 

  119. Scammell, T. et al. Activation of ventrolateral preoptic neurons by the somnogen prostaglandin D2. Proc. Natl Acad. Sci. USA 95, 7754–7759 (1998)

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  120. Mizoguchi, A. et al. Dominant localization of prostaglandin D receptors on arachnoid trabecular cells in mouse basal forebrain and their involvement in the regulation of non-rapid eye movement sleep. Proc. Natl Acad. Sci. USA 98, 11674–11679 (2001)

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  121. Huber, R., Ghilardi, M. F., Massimini, M. & Tononi, G. Local sleep and learning. Nature 430, 78–81 (2004)

    ADS  CAS  PubMed  Article  Google Scholar 

  122. Vyazovskiy, V., Borbély, A. A. & Tobler, I. Unilateral vibrissae stimulation during waking induces interhemispheric EEG asymmetry during subsequent sleep in the rat. J. Sleep Res. 9, 367–371 (2000)

    CAS  PubMed  Article  Google Scholar 

  123. Gerashchenko, D. et al. Identification of a population of sleep-active cerebral cortex neurons. Proc. Natl Acad. Sci. USA 105, 10227–10232 (2008).This study reported sleep-active, nNOS expressing neurons in the cortex. As c-Fos activation correlates with sleep pressure, these neurons might be involved in the cortical expression of sleep homeostasis.

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  124. Morairty, S. R. et al. A role for cortical nNOS/NK1 neurons in coupling homeostatic sleep drive to EEG slow wave activity. Proc. Natl Acad. Sci. USA 110, 20272–20277 (2013)

    ADS  CAS  PubMed  Article  PubMed Central  Google Scholar 

  125. Seress, L., Abrahám, H., Hajnal, A., Lin, H. & Totterdell, S. NOS-positive local circuit neurons are exclusively axo-dendritic cells both in the neo- and archi-cortex of the rat brain. Brain Res. 1056, 183–190 (2005)

    CAS  PubMed  Article  Google Scholar 

  126. Benington, J. H. & Heller, H. C. REM-sleep timing is controlled homeostatically by accumulation of REM-sleep propensity in non-REM sleep. Am. J. Physiol. 266, R1992–R2000 (1994)

    CAS  PubMed  Google Scholar 

  127. Franken, P. Long-term vs. short-term processes regulating REM sleep. J. Sleep Res. 11, 17–28 (2002)

    PubMed  Article  Google Scholar 

  128. Chou, T. C. et al. Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms. J. Neurosci. 23, 10691–10702 (2003)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. Wurts, S. W. & Edgar, D. M. Circadian and homeostatic control of rapid eye movement (REM) sleep: promotion of REM tendency by the suprachiasmatic nucleus. J. Neurosci. 20, 4300–4310 (2000)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. Jones, J. R., Tackenberg, M. C. & McMahon, D. G. Manipulating circadian clock neuron firing rate resets molecular circadian rhythms and behavior. Nat. Neurosci. 18, 373–375 (2015)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. King, D. P. & Takahashi, J. S. Molecular genetics of circadian rhythms in mammals. Annu. Rev. Neurosci. 23, 713–742 (2000)

    CAS  PubMed  Article  Google Scholar 

  132. Flourakis, M. et al. A conserved bicycle model for circadian clock control of membrane excitability. Cell 162, 836–848 (2015)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. Hattar, S., Liao, H. W., Takao, M., Berson, D. M. & Yau, K. W. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 295, 1065–1070 (2002)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. Deboer, T., Vansteensel, M. J., Détári, L. & Meijer, J. H. Sleep states alter activity of suprachiasmatic nucleus neurons. Nat. Neurosci. 6, 1086–1090 (2003)

    CAS  PubMed  Article  Google Scholar 

  135. Bina, K. G., Rusak, B. & Semba, K. Localization of cholinergic neurons in the forebrain and brainstem that project to the suprachiasmatic nucleus of the hypothalamus in rat. J. Comp. Neurol. 335, 295–307 (1993)

    CAS  PubMed  Article  Google Scholar 

  136. Meyer-Bernstein, E. L., Blanchard, J. H. & Morin, L. P. The serotonergic projection from the median raphe nucleus to the suprachiasmatic nucleus modulates activity phase onset, but not other circadian rhythm parameters. Brain Res. 755, 112–120 (1997)

    CAS  PubMed  Article  Google Scholar 

  137. Aston-Jones, G., Chen, S., Zhu, Y. & Oshinsky, M. L. A neural circuit for circadian regulation of arousal. Nat. Neurosci. 4, 732–738 (2001)

    CAS  PubMed  Article  Google Scholar 

  138. Carter, M. E. et al. Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat. Neurosci. 13, 1526–1533 (2010)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. Halassa, M. M. et al. State-dependent architecture of thalamic reticular subnetworks. Cell 158, 808–821 (2014)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. Rossi, M. et al. Investigation of the feeding effects of melanin concentrating hormone on food intake--action independent of galanin and the melanocortin receptors. Brain Res. 846, 164–170 (1999)

    ADS  CAS  PubMed  Article  Google Scholar 

  141. Kemp, B., Zwinderman, A. H., Tuk, B., Kamphuisen, H. A. & Oberyé, J. J. Analysis of a sleep-dependent neuronal feedback loop: the slow-wave microcontinuity of the EEG. IEEE Trans. Biomed. Eng. 47, 1185–1194 (2000)

    CAS  PubMed  Article  Google Scholar 

  142. Goldberger, A. L. et al. PhysioBank, PhysioToolkit, and PhysioNet: components of a new research resource for complex physiologic signals. Circulation 101, e215–e220 (2000)

    CAS  PubMed  Google Scholar 

  143. Berndt, A. et al. Structural foundations of optogenetics: determinants of channelrhodopsin ion selectivity. Proc. Natl Acad. Sci. USA 113, 822–829 (2016)

    ADS  CAS  PubMed  Article  Google Scholar 

  144. Buch, T. et al. A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nat. Methods 2, 419–426 (2005)

    CAS  PubMed  Article  Google Scholar 

  145. Morgan, C. W., Julien, O., Unger, E. K., Shah, N. M. & Wells, J. A. Turning on caspases with genetics and small molecules. Methods Enzymol. 544, 179–213 (2014)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

We thank Z. Zhang for providing a 24 h sleep recording from a mouse and S. Chung for helpful comments on the manuscript. This work was supported by EMBO and Human Frontier Science Program postdoctoral fellowships (to F.W.).

Author information

Authors and Affiliations

Authors

Contributions

F.W. and Y.D. wrote and revised the manuscript.

Corresponding author

Correspondence to Yang Dan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Reviewer Information

Nature thanks J. Born and the other anonymous reviewer(s) for their contribution to the peer review of this work.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Weber, F., Dan, Y. Circuit-based interrogation of sleep control. Nature 538, 51–59 (2016). https://doi.org/10.1038/nature19773

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature19773

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing