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Insomnia-related rodent models in drug discovery

Acta Pharmacologica Sinica volume 45, pages 1777–1792 (2024)Cite this article

Abstract

Despite the widespread prevalence and important medical impact of insomnia, effective agents with few side effects are lacking in clinics. This is most likely due to relatively poor understanding of the etiology and pathophysiology of insomnia, and the lack of appropriate animal models for screening new compounds. As the main homeostatic, circadian, and neurochemical modulations of sleep remain essentially similar between humans and rodents, rodent models are often used to elucidate the mechanisms of insomnia and to develop novel therapeutic targets. In this article, we focus on several rodent models of insomnia induced by stress, diseases, drugs, disruption of the circadian clock, and other means such as genetic manipulation of specific neuronal activity, respectively, which could be used to screen for novel hypnotics. Moreover, important advantages and constraints of some animal models are discussed. Finally, this review highlights that the rodent models of insomnia may play a crucial role in novel drug development to optimize the management of insomnia.

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Fig. 1: Modeling of insomnia in rodents.

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References

  1. Bao WW, Jiang S, Qu WM, Li WX, Miao CH, Huang ZL. Understanding the neural mechanisms of general anesthesia from interaction with sleep-wake state: a decade of discovery. Pharmacol Rev. 2023;75:532–53.

    Article  PubMed  CAS  Google Scholar 

  2. Wang YQ, Liu WY, Li L, Qu WM, Huang ZL. Neural circuitry underlying rem sleep: a review of the literature and current concepts. Prog Neurobiol. 2021;204:102106.

    Article  PubMed  CAS  Google Scholar 

  3. Liu D, Dan Y. A motor theory of sleep-wake control: arousal-action circuit. Annu Rev Neurosci. 2019;42:27–46.

    Article  PubMed  CAS  Google Scholar 

  4. Bhaskar S, Hemavathy D, Prasad S. Prevalence of chronic insomnia in adult patients and its correlation with medical comorbidities. J Fam Med Prim Care. 2016;5:780–4.

    Article  Google Scholar 

  5. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4:487–504.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Benca RM. Diagnosis and treatment of chronic insomnia: a review. Psychiatr Serv. 2005;56:332–43.

    Article  PubMed  Google Scholar 

  7. Revel FG, Gottowik J, Gatti S, Wettstein JG, Moreau JL. Rodent models of insomnia: a review of experimental procedures that induce sleep disturbances. Neurosci Biobehav Rev. 2009;33:874–99.

    Article  PubMed  Google Scholar 

  8. Wilt TJ, MacDonald R, Brasure M, Olson CM, Carlyle M, Fuchs E, et al. Pharmacologic treatment of insomnia disorder: An evidence report for a clinical practice guideline by the american college of physicians. Ann Intern Med. 2016;165:103–12.

    Article  PubMed  Google Scholar 

  9. Costentin J. [treatment of insomnia. Pharmacological approaches and their limitations]. Bull Acad Natl Med. 2011;195:1583–94.

    PubMed  CAS  Google Scholar 

  10. Gunja N. The clinical and forensic toxicology of Z-drugs. J Med Toxicol. 2013;9:155–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Morin AK. Strategies for treating chronic insomnia. Am J Manag Care. 2006;12:S230–45.

    PubMed  Google Scholar 

  12. Glass J, Lanctot KL, Herrmann N, Sproule BA, Busto UE. Sedative hypnotics in older people with insomnia: Meta-analysis of risks and benefits. BMJ. 2005;331:1169.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Spadoni G, Bedini A, Rivara S, Mor M. Melatonin receptor agonists: New options for insomnia and depression treatment. CNS Neurosci Ther. 2011;17:733–41.

    Article  PubMed  CAS  Google Scholar 

  14. Yeung WF, Chung KF, Yung KP, Ng TH. Doxepin for insomnia: A systematic review of randomized placebo-controlled trials. Sleep Med Rev. 2015;19:75–83.

    Article  PubMed  Google Scholar 

  15. Kay-Stacey M, Attarian H. Advances in the management of chronic insomnia. BMJ. 2016;354:i2123.

    Article  PubMed  Google Scholar 

  16. Veasey SC, Valladares O, Fenik P, Kapfhamer D, Sanford L, Benington J, et al. An automated system for recording and analysis of sleep in mice. Sleep. 2000;23:1025–40.

    Article  PubMed  CAS  Google Scholar 

  17. Paterson LM, Nutt DJ, Wilson SJ. Sleep and its disorders in translational medicine. J Psychopharmacol. 2011;25:1226–34.

    Article  PubMed  CAS  Google Scholar 

  18. Rea MS, Bierman A, Figueiro MG, Bullough JD. A new approach to understanding the impact of circadian disruption on human health. J Circadian Rhythms. 2008;6:7.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wisor JP, Jiang P, Striz M, O’Hara BF. Effects of ramelteon and triazolam in a mouse genetic model of early morning awakenings. Brain Res. 2009;1296:46–55.

    Article  PubMed  CAS  Google Scholar 

  20. Wafford KA, Ebert B. Emerging anti-insomnia drugs: Tackling sleeplessness and the quality of wake time. Nat Rev Drug Discov. 2008;7:530–40.

    Article  PubMed  CAS  Google Scholar 

  21. Lee DH, Cho CH, Han C, Bok KN, Moon JH, Lee E, et al. Sleep irregularity in the previous week influences the first-night effect in polysomnographic studies. Psychiatry Investig. 2016;13:203–9.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Toussaint M, Luthringer R, Schaltenbrand N, Carelli G, Lainey E, Jacqmin A, et al. First-night effect in normal subjects and psychiatric inpatients. Sleep. 1995;18:463–9.

    Article  PubMed  CAS  Google Scholar 

  23. Tang X, Xiao J, Parris BS, Fang J, Sanford LD. Differential effects of two types of environmental novelty on activity and sleep in BALB/cJ and C57BL/6J mice. Physiol Behav. 2005;85:419–29.

    Article  PubMed  CAS  Google Scholar 

  24. Xu Q, Xu XH, Qu WM, Lazarus M, Urade Y, Huang ZL. A mouse model mimicking human first night effect for the evaluation of hypnotics. Pharmacol Biochem Behav. 2014;116:129–36.

    Article  PubMed  CAS  Google Scholar 

  25. McKenna JT, Gamble MC, Anderson-Chernishof MB, Shah SR, McCoy JG, Strecker RE. A rodent cage change insomnia model disrupts memory consolidation. J Sleep Res. 2019;28:e12792.

    Article  PubMed  Google Scholar 

  26. Sanford LD, Yang L, Wellman LL, Liu X, Tang X. Differential effects of controllable and uncontrollable footshock stress on sleep in mice. Sleep. 2010;33:621–30.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wellman LL, Yang L, Sanford LD. Effects of corticotropin releasing factor (CRF) on sleep and temperature following predictable controllable and uncontrollable stress in mice. Front Neurosci. 2015;9:258.

    Article  PubMed  PubMed Central  Google Scholar 

  28. O’Malley MW, Fishman RL, Ciraulo DA, Datta S. Effect of five-consecutive-day exposure to an anxiogenic stressor on sleep-wake activity in rats. Front Neurol. 2013;4:15.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Philbert J, Beeske S, Belzung C, Griebel G. The CRF(1) receptor antagonist SSR125543 prevents stress-induced long-lasting sleep disturbances in a mouse model of PTSD: Comparison with paroxetine and d-cycloserine. Behav Brain Res. 2015;279:41–6.

    Article  PubMed  CAS  Google Scholar 

  30. Machida M, Wellman LL, Fitzpatrick Bs ME, Hallum Bs O, Sutton Bs AM, Lonart G, et al. Effects of optogenetic inhibition of BLA on sleep brief optogenetic inhibition of the basolateral amygdala in mice alters effects of stressful experiences on rapid eye movement sleep. Sleep. 2017;40:zsx020.

    PubMed  PubMed Central  Google Scholar 

  31. Philbert J, Pichat P, Beeske S, Decobert M, Belzung C, Griebel G. Acute inescapable stress exposure induces long-term sleep disturbances and avoidance behavior: A mouse model of post-traumatic stress disorder (PTSD). Behav Brain Res. 2011;221:149–54.

    Article  PubMed  CAS  Google Scholar 

  32. Yu B, Cui SY, Zhang XQ, Cui XY, Li SJ, Sheng ZF, et al. Mechanisms underlying footshock and psychological stress-induced abrupt awakening from posttraumatic “nightmares”. Int J Neuropsychopharmacol. 2016;19:pyv113.

    Article  PubMed  Google Scholar 

  33. Oishi K, Nishio N, Konishi K, Shimokawa M, Okuda T, Kuriyama T, et al. Differential effects of physical and psychological stressors on immune functions of rats. Stress. 2003;6:33–40.

    Article  PubMed  CAS  Google Scholar 

  34. Endo Y, Shiraki K. Behavior and body temperature in rats following chronic foot shock or psychological stress exposure. Physiol Behav. 2000;71:263–8.

    Article  PubMed  CAS  Google Scholar 

  35. Cui R, Suemaru K, Li B, Araki H. The effects of atropine on changes in the sleep patterns induced by psychological stress in rats. Eur J Pharmacol. 2008;579:153–9.

    Article  PubMed  CAS  Google Scholar 

  36. Cui R, Li B, Suemaru K, Araki H. Differential effects of psychological and physical stress on the sleep pattern in rats. Acta Med Okayama. 2007;61:319–27.

    PubMed  Google Scholar 

  37. Cui R, Li B, Suemaru K, Araki H. The effect of baclofen on alterations in the sleep patterns induced by different stressors in rats. J Pharm Sci. 2009;109:518–24.

    Article  CAS  Google Scholar 

  38. Roth T, van Seventer R, Murphy TK. The effect of pregabalin on pain-related sleep interference in diabetic peripheral neuropathy or postherpetic neuralgia: A review of nine clinical trials. Curr Med Res Opin. 2010;26:2411–9.

    Article  PubMed  CAS  Google Scholar 

  39. Keilani M, Crevenna R, Dorner T. Sleep quality in subjects suffering from chronic pain. Wien Klin Wochenschr. 2018;130:31–6.

    Article  PubMed  Google Scholar 

  40. Li YD, Luo YJ, Su WK, Ge J, Crowther A, Chen ZK, et al. Anterior cingulate cortex projections to the dorsal medial striatum underlie insomnia associated with chronic pain. Neuron. 2024:S0896-6273(24)00040-0.

  41. Tokunaga S, Takeda Y, Shinomiya K, Yamamo’ro W, Utsu Y, Toide K, et al. Changes of sleep patterns in rats with chronic constriction injury under aversive conditions. Biol Pharm Bull. 2007;30:2088–90.

    Article  PubMed  CAS  Google Scholar 

  42. Kontinen VK, Ahnaou A, Drinkenburg WHIM, Meert TF. Sleep and eeg patterns in the chronic constriction injury model of neuropathic pain. Physiol Behav. 2003;78:241–6.

    Article  PubMed  CAS  Google Scholar 

  43. Liu YY, Yin D, Chen L, Qu WM, Chen CR, Laudon M, et al. Piromelatine exerts antinociceptive effect via melatonin, opioid, and 5HT(1a) receptors and hypnotic effect via melatonin receptors in a mouse model of neuropathic pain. Psychopharmacology. 2014;231:3973–85.

    Article  PubMed  CAS  Google Scholar 

  44. Yin D, Liu YY, Wang TX, Hu ZZ, Qu WM, Chen JF, et al. Paeoniflorin exerts analgesic and hypnotic effects via adenosine A (1) receptors in a mouse neuropathic pain model. Psychopharmacology. 2016;233:281–93.

    Article  PubMed  CAS  Google Scholar 

  45. Wang TX, Yin D, Guo W, Liu YY, Li YD, Qu WM, et al. Antinociceptive and hypnotic activities of pregabalin in a neuropathic pain-like model in mice. Pharmacol Biochem Behav. 2015;135:31–9.

    Article  PubMed  CAS  Google Scholar 

  46. Narita M, Niikura K, Nanjo-Niikura K, Furuya M, Yamashita A, Saeki M, et al. Sleep disturbances in a neuropathic pain-like condition in the mouse are associated with altered gabaergic transmission in the cingulate cortex. Pain. 2011;152:1358–72.

    Article  PubMed  CAS  Google Scholar 

  47. Andersen ML, Tufik S. Altered sleep and behavioral patterns of arthritic rats. Sleep Res Online. 2000;3:161–7.

    PubMed  CAS  Google Scholar 

  48. Yang CCH, Huang SS, Lai CT, Kuo TBJ, Chu YC. Changes in sleep architecture under sustained pain in adult male rats subjected to neonatal short-lasting local inflammatory insult. Dev Neurosci. 2017;39:386–98.

    Article  PubMed  CAS  Google Scholar 

  49. Rabat A, Bouyer JJ, Aran JM, Le Moal M, Mayo W. Chronic exposure to an environmental noise permanently disturbs sleep in rats: Inter-individual vulnerability. Brain Res. 2005;1059:72–82.

    Article  PubMed  CAS  Google Scholar 

  50. Rabat A, Bouyer JJ, George O, Le Moal M, Mayo W. Chronic exposure of rats to noise: Relationship between long-term memory deficits and slow wave sleep disturbances. Behav Brain Res. 2006;171:303–12.

    Article  PubMed  CAS  Google Scholar 

  51. Rabat A, Bouyer JJ, Aran JM, Courtiere A, Mayo W, Le Moal M. Deleterious effects of an environmental noise on sleep and contribution of its physical components in a rat model. Brain Res. 2004;1009:88–97.

    Article  PubMed  CAS  Google Scholar 

  52. Thiessen GJ, Lapointe AC. Effect of continuous traffic noise on percentage of deep sleep, waking, and sleep latency. J Acoust Soc Am. 1983;73:225–9.

    Article  PubMed  CAS  Google Scholar 

  53. Thiessen GJ, Lapointe AC. Effect of intermittent truck noise on percentage of deep sleep. J Acoust Soc Am. 1978;64:1078–80.

    Article  PubMed  CAS  Google Scholar 

  54. Ebben MR, Yan P, Krieger AC. The effects of white noise on sleep and duration in individuals living in a high noise environment in New York city. Sleep Med. 2021;83:256–9.

    Article  PubMed  Google Scholar 

  55. Colavito V, Fabene PF, Grassi-Zucconi G, Pifferi F, Lamberty Y, Bentivoglio M, et al. Experimental sleep deprivation as a tool to test memory deficits in rodents. Front Syst Neurosci. 2013;7:106.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Borbely AA, Tobler I, Hanagasioglu M. Effect of sleep deprivation on sleep and eeg power spectra in the rat. Behav Brain Res. 1984;14:171–82.

    Article  PubMed  CAS  Google Scholar 

  57. Kaidanovich-Beilin O, Lipina T, Vukobradovic I, Roder J, Woodgett JR. Assessment of social interaction behaviors. J Vis Exp. 2011;48:2473.

    Google Scholar 

  58. Gompf HS, Mathai C, Fuller PM, Wood DA, Pedersen NP, Saper CB, et al. Locus ceruleus and anterior cingulate cortex sustain wakefulness in a novel environment. J Neurosci. 2010;30:14543–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Bjorkqvist K. Social defeat as a stressor in humans. Physiol Behav. 2001;73:435–42.

    Article  PubMed  CAS  Google Scholar 

  60. Nielsen MB, Harris A, Pallesen S, Einarsen SV. Workplace bullying and sleep - a systematic review and meta-analysis of the research literature. Sleep Med Rev. 2020;51:101289.

    Article  PubMed  Google Scholar 

  61. Fujii S, Kaushik MK, Zhou X, Korkutata M, Lazarus M. Acute social defeat stress increases sleep in mice. Front Neurosci. 2019;13:322.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Ahnaou A, Drinkenburg WH. Simultaneous changes in sleep, qeeg, physiology, behaviour and neurochemistry in rats exposed to repeated social defeat stress. Neuropsychobiology. 2016;73:209–23.

    Article  PubMed  CAS  Google Scholar 

  63. Sharma R, Sahota P, Thakkar MM. Severe and protracted sleep disruptions in mouse model of post-traumatic stress disorder. Sleep. 2018;41:1–12.

  64. Gonzalez MM, Debilly G, Valatx JL, Jouvet M. Sleep increase after immobilization stress: Role of the noradrenergic locus coeruleus system in the rat. Neurosci Lett. 1995;202:5–8.

    Article  PubMed  CAS  Google Scholar 

  65. Papale LA, Andersen ML, Antunes IB, Alvarenga TA, Tufik S. Sleep pattern in rats under different stress modalities. Brain Res. 2005;1060:47–54.

    Article  PubMed  CAS  Google Scholar 

  66. Valdes JL, Sanchez C, Riveros ME, Blandina P, Contreras M, Farias P, et al. The histaminergic tuberomammillary nucleus is critical for motivated arousal. Eur J Neurosci. 2010;31:2073–85.

    Article  PubMed  Google Scholar 

  67. Wang YQ, Li R, Wu X, Zhu F, Takata Y, Zhang Z, et al. Fasting activated histaminergic neurons and enhanced arousal effect of caffeine in mice. Pharmacol Biochem Behav. 2015;133:164–73.

    Article  PubMed  CAS  Google Scholar 

  68. Almeneessier AS, Alzoghaibi M, BaHammam AA, Ibrahim MG, Olaish AH, Nashwan SZ, et al. The effects of diurnal intermittent fasting on the wake-promoting neurotransmitter orexin-A. Ann Thorac Med. 2018;13:48–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Schmid SM, Hallschmid M, Jauch-Chara K, Born J, Schultes B. A single night of sleep deprivation increases ghrelin levels and feelings of hunger in normal-weight healthy men. J Sleep Res. 2008;17:331–4.

    Article  PubMed  Google Scholar 

  70. Kumar A, Kalonia H. Protective effect of withania somnifera dunal on the behavioral and biochemical alterations in sleep-disturbed mice (grid over water suspended method). Indian J Exp Biol. 2007;45:524–8.

    PubMed  Google Scholar 

  71. Shinomiya K, Shigemoto Y, Okuma C, Mio M, Kamei C. Effects of short-acting hypnotics on sleep latency in rats placed on grid suspended over water. Eur J Pharmacol. 2003;460:139–44.

    Article  PubMed  CAS  Google Scholar 

  72. Utsu Y, Shinomiya K, Tokunaga S, Ohmori A, Kamei C. Effect of tandospirone on sleep latency in rats placed on a grid suspended over water. J Pharmacol Sci. 2007;105:112–6.

    Article  PubMed  CAS  Google Scholar 

  73. Spano GM, Banningh SW, Marshall W, de Vivo L, Bellesi M, Loschky SS, et al. Sleep deprivation by exposure to novel objects increases synapse density and axon-spine interface in the hippocampal CA1 region of adolescent mice. J Neurosci. 2019;39:6613–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Brownlow JA, Harb GC, Ross RJ. Treatment of sleep disturbances in post-traumatic stress disorder: a review of the literature. Curr Psychiatry Rep. 2015;17:41.

    Article  PubMed  Google Scholar 

  75. Moldofsky H, Rothman L, Kleinman R, Rhind SG, Richardson JD. Disturbed eeg sleep, paranoid cognition and somatic symptoms identify veterans with post-traumatic stress disorder. BJPsych Open. 2016;2:359–65.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Mellman TA, Bustamante V, Fins AI, Pigeon WR, Nolan B. Rem sleep and the early development of posttraumatic stress disorder. Am J Psychiatry. 2002;159:1696–701.

    Article  PubMed  Google Scholar 

  77. Goswami S, Rodriguez-Sierra O, Cascardi M, Pare D. Animal models of post-traumatic stress disorder: Face validity. Front Neurosci. 2013;7:89.

    Article  PubMed  PubMed Central  Google Scholar 

  78. American Psychiatric Association D, Association AP. Diagnostic and statistical manual of mental disorders: DSM-5. (American psychiatric association Washington, DC, 2013), 5.

  79. Nedelcovych MT, Gould RW, Zhan X, Bubser M, Gong X, Grannan M, et al. A rodent model of traumatic stress induces lasting sleep and quantitative electroencephalographic disturbances. ACS Chem Neurosci. 2015;6:485–93.

    Article  PubMed  CAS  Google Scholar 

  80. Ameratunga D, Goldin J, Hickey M. Sleep disturbance in menopause. Intern Med J. 2012;42:742–7.

    Article  PubMed  CAS  Google Scholar 

  81. Shaver JL, Woods NF. Sleep and menopause: a narrative review. Menopause. 2015;22:899–915.

    Article  PubMed  Google Scholar 

  82. Polo-Kantola P. Sleep problems in midlife and beyond. Maturitas. 2011;68:224–32.

    Article  PubMed  Google Scholar 

  83. Kravitz HM, Zhao X, Bromberger JT, Gold EB, Hall MH, Matthews KA, et al. Sleep disturbance during the menopausal transition in a multi-ethnic community sample of women. Sleep. 2008;31:979–90.

    PubMed  PubMed Central  Google Scholar 

  84. Baker FC, de Zambotti M, Colrain IM, Bei B. Sleep problems during the menopausal transition: prevalence, impact, and management challenges. Nat Sci Sleep. 2018;10:73–95.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Kravitz HM, Ganz PA, Bromberger J, Powell LH, Sutton-Tyrrell K, Meyer PM. Sleep difficulty in women at midlife: a community survey of sleep and the menopausal transition. Menopause. 2003;10:19–28.

    PubMed  Google Scholar 

  86. Koebele SV, Bimonte-Nelson HA. Modeling menopause: the utility of rodents in translational behavioral endocrinology research. Maturitas. 2016;87:5–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Deurveilher S, Rusak B, Semba K. Female reproductive hormones alter sleep architecture in ovariectomized rats. Sleep. 2011;34:519–30.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Fang J, Fishbein W. Sex differences in paradoxical sleep: Influences of estrus cycle and ovariectomy. Brain Res. 1996;734:275–85.

    Article  PubMed  CAS  Google Scholar 

  89. Mayer LP, Devine PJ, Dyer CA, Hoyer PB. The follicle-deplete mouse ovary produces androgen. Biol Reprod. 2004;71:130–8.

    Article  PubMed  CAS  Google Scholar 

  90. Springer LN, McAsey ME, Flaws JA, Tilly JL, Sipes IG, Hoyer PB. Involvement of apoptosis in 4-vinylcyclohexene diepoxide-induced ovotoxicity in rats. Toxicol Appl Pharmacol. 1996;139:394–401.

    Article  PubMed  CAS  Google Scholar 

  91. Van Kempen TA, Milner TA, Waters EM. Accelerated ovarian failure: a novel, chemically induced animal model of menopause. Brain Res. 2011;1379:176–87.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Yu S, Zhang L, Wang Y, Yan J, Wang Q, Bian H, et al. Mood, hormone levels, metabolic and sleep across the menopausal transition in vcd-induced icr mice. Physiol Behav. 2023;265:114178.

    Article  PubMed  CAS  Google Scholar 

  93. Wang YQ, Li R, Zhang MQ, Zhang Z, Qu WM, Huang ZL. The neurobiological mechanisms and treatments of rem sleep disturbances in depression. Curr Neuropharmacol. 2015;13:543–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Steiger A, Pawlowski M. Depression and sleep. Int J Mol Sci. 2019;20:607.

  95. Nutt D, Wilson S, Paterson L. Sleep disorders as core symptoms of depression. Dialogues Clin Neurosci. 2008;10:329–36.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Wang YQ, Tu ZC, Xu XY, Li R, Qu WM, Urade Y, et al. Acute administration of fluoxetine normalizes rapid eye movement sleep abnormality, but not depressive behaviors in olfactory bulbectomized rats. J Neurochem. 2012;120:314–24.

    Article  PubMed  Google Scholar 

  97. Chikahisa S, Harada S, Shimizu N, Shiuchi T, Otsuka A, Nishino S, et al. Mast cell involvement in glucose tolerance impairment caused by chronic mild stress with sleep disturbance. Sci Rep. 2017;7:13640.

    Article  PubMed  PubMed Central  Google Scholar 

  98. El Yacoubi M, Bouali S, Popa D, Naudon L, Leroux-Nicollet I, Hamon M, et al. Behavioral, neurochemical, and electrophysiological characterization of a genetic mouse model of depression. Proc Natl Acad Sci USA. 2003;100:6227–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Popa D, El Yacoubi M, Vaugeois JM, Hamon M, Adrien J. Homeostatic regulation of sleep in a genetic model of depression in the mouse: Effects of muscarinic and 5-HT1A receptor activation. Neuropsychopharmacology. 2006;31:1637–46.

    Article  PubMed  CAS  Google Scholar 

  100. Peter-Derex L, Yammine P, Bastuji H, Croisile B. Sleep and Alzheimer’s disease. Sleep Med Rev. 2015;19:29–38.

    Article  PubMed  Google Scholar 

  101. Guarnieri B, Adorni F, Musicco M, Appollonio I, Bonanni E, Caffarra P, et al. Prevalence of sleep disturbances in mild cognitive impairment and dementing disorders: A multicenter italian clinical cross-sectional study on 431 patients. Dement Geriatr Cogn Disord. 2012;33:50–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Benedict C, Byberg L, Cedernaes J, Hogenkamp PS, Giedratis V, Kilander L, et al. Self-reported sleep disturbance is associated with Alzheimer’s disease risk in men. Alzheimers Dement. 2015;11:1090–7.

    Article  PubMed  Google Scholar 

  103. Ju YE, Lucey BP, Holtzman DM. Sleep and Alzheimer disease pathology–a bidirectional relationship. Nat Rev Neurol. 2014;10:115–9.

    Article  PubMed  CAS  Google Scholar 

  104. Wisor JP, Edgar DM, Yesavage J, Ryan HS, McCormick CM, Lapustea N, et al. Sleep and circadian abnormalities in a transgenic mouse model of Alzheimer’s disease: a role for cholinergic transmission. Neuroscience. 2005;131:375–85.

    Article  PubMed  CAS  Google Scholar 

  105. Kam K, Duffy AM, Moretto J, LaFrancois JJ, Scharfman HE. Interictal spikes during sleep are an early defect in the Tg2576 mouse model of beta-amyloid neuropathology. Sci Rep. 2016;6:20119.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Zhang B, Veasey SC, Wood MA, Leng LZ, Kaminski C, Leight S, et al. Impaired rapid eye movement sleep in the Tg2576 APP murine model of Alzheimer’s disease with injury to pedunculopontine cholinergic neurons. Am J Pathol. 2005;167:1361–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Colby-Milley J, Cavanagh C, Jego S, Breitner JC, Quirion R, Adamantidis A. Sleep-wake cycle dysfunction in the TgCRND8 mouse model of Alzheimer’s disease: From early to advanced pathological stages. PLoS One. 2015;10:e0130177.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Sethi M, Joshi SS, Webb RL, Beckett TL, Donohue KD, Murphy MP, et al. Increased fragmentation of sleep-wake cycles in the 5XFAD mouse model of Alzheimer’s disease. Neuroscience. 2015;290:80–9.

    Article  PubMed  CAS  Google Scholar 

  109. Roh JH, Huang Y, Bero AW, Kasten T, Stewart FR, Bateman RJ, et al. Disruption of the sleep-wake cycle and diurnal fluctuation of beta-amyloid in mice with Alzheimer’s disease pathology. Sci Transl Med. 2012;4:150ra22.

    Article  Google Scholar 

  110. Sixel-Doring F, Schweitzer M, Mollenhauer B, Trenkwalder C. Intraindividual variability of REM sleep behavior disorder in Parkinson’s disease: a comparative assessment using a new REM sleep behavior disorder severity scale (RBDSS) for clinical routine. J Clin Sleep Med. 2011;7:75–80.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Tandberg E, Larsen JP, Karlsen K. A community-based study of sleep disorders in patients with Parkinson’s disease. Mov Disord. 1998;13:895–9.

    Article  PubMed  CAS  Google Scholar 

  112. Suzuki K, Miyamoto M, Miyamoto T, Hirata K. Parkinson’s disease and sleep/wake disturbances. Curr Neurol Neurosci Rep. 2015;15:8.

    Article  PubMed  Google Scholar 

  113. Adler CH, Thorpy MJ. Sleep issues in Parkinson’s disease. Neurology. 2005;64:S12–20.

    Article  PubMed  Google Scholar 

  114. Alam M, Schmidt WJ. Rotenone destroys dopaminergic neurons and induces Parkinsonian symptoms in rats. Behav Brain Res. 2002;136:317–24.

    Article  PubMed  CAS  Google Scholar 

  115. Zuch CL, Nordstroem VK, Briedrick LA, Hoernig GR, Granholm AC, Bickford PC. Time course of degenerative alterations in nigral dopaminergic neurons following a 6-hydroxydopamine lesion. J Comp Neurol. 2000;427:440–54.

    Article  PubMed  CAS  Google Scholar 

  116. Fornai F, Schluter OM, Lenzi P, Gesi M, Ruffoli R, Ferrucci M, et al. Parkinson-like syndrome induced by continuous mptp infusion: Convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc Natl Acad Sci USA. 2005;102:3413–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Vo Q, Gilmour TP, Venkiteswaran K, Fang J, Subramanian T. Polysomnographic features of sleep disturbances and rem sleep behavior disorder in the unilateral 6-OHDA lesioned hemiparkinsonian rat. Parkinsons Dis. 2014;2014:852965.

    PubMed  PubMed Central  Google Scholar 

  118. Monaca C, Laloux C, Jacquesson JM, Gele P, Marechal X, Bordet R, et al. Vigilance states in a parkinsonian model, the MPTP mouse. Eur J Neurosci. 2004;20:2474–8.

    Article  PubMed  Google Scholar 

  119. Lima MM, Andersen ML, Reksidler AB, Vital MA, Tufik S. The role of the substantia nigra pars compacta in regulating sleep patterns in rats. PLoS One. 2007;2:e513.

    Article  PubMed  PubMed Central  Google Scholar 

  120. McDowell KA, Hadjimarkou MM, Viechweg S, Rose AE, Clark SM, Yarowsky PJ, et al. Sleep alterations in an environmental neurotoxin-induced model of parkinsonism. Exp Neurol. 2010;226:84–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Yi PL, Tsai CH, Lu MK, Liu HJ, Chen YC, Chang FC. Interleukin-1beta mediates sleep alteration in rats with rotenone-induced parkinsonism. Sleep. 2007;30:413–25.

    Article  PubMed  Google Scholar 

  122. Dawson TM, Ko HS, Dawson VL. Genetic animal models of parkinson’s disease. Neuron. 2010;66:646–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Chesselet MF, Richter F, Zhu C, Magen I, Watson MB, Subramaniam SR. A progressive mouse model of parkinson’s disease: the thy1-asyn (“line 61”) mice. Neurotherapeutics. 2012;9:297–314.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. McDowell KA, Shin D, Roos KP, Chesselet MF. Sleep dysfunction and eeg alterations in mice overexpressing alpha-synuclein. J Parkinsons Dis. 2014;4:531–9.

    Article  PubMed  CAS  Google Scholar 

  125. Shen Y, Yu WB, Shen B, Dong H, Zhao J, Tang YL, et al. Propagated alpha-synucleinopathy recapitulates rem sleep behaviour disorder followed by parkinsonian phenotypes in mice. Brain. 2020;143:3374–92.

    Article  PubMed  Google Scholar 

  126. Zeman A, Britton T, Douglas N, Hansen A, Hicks J, Howard R, et al. Narcolepsy and excessive daytime sleepiness. BMJ. 2004;329:724–8.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Andlauer O, Moore H, Jouhier L, Drake C, Peppard PE, Han F, et al. Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy/hypocretin deficiency. JAMA Neurol. 2013;70:891–902.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Kim LJ, Coelho FM, Hirotsu C, Araujo P, Bittencourt L, Tufik S, et al. Frequencies and associations of narcolepsy-related symptoms: A cross-sectional study. J Clin Sleep Med. 2015;11:1377–84.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Kumar S, Sagili H. Etiopathogenesis and neurobiology of narcolepsy: a review. J Clin Diagn Res. 2014;8:190–5.

    PubMed  Google Scholar 

  130. Hung CJ, Ono D, Kilduff TS, Yamanaka A. Dual orexin and MCH neuron-ablated mice display severe sleep attacks and cataplexy. Elife. 2020;9:e54275.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Chen ZK, Dong H, Liu CW, Liu WY, Zhao YN, Xu W, et al. A cluster of mesopontine gabaergic neurons suppresses rem sleep and curbs cataplexy. Cell Discov. 2022;8:115.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Huang ZL, Zhang Z, Qu WM. Roles of adenosine and its receptors in sleep-wake regulation. Int Rev Neurobiol. 2014;119:349–71.

    Article  PubMed  Google Scholar 

  133. Hayaishi O, Urade Y, Eguchi N, Huang ZL. Genes for prostaglandin d synthase and receptor as well as adenosine A2A receptor are involved in the homeostatic regulation of NREM sleep. Arch Ital Biol. 2004;142:533–9.

    PubMed  CAS  Google Scholar 

  134. Clark I, Landolt HP. Coffee, caffeine, and sleep: a systematic review of epidemiological studies and randomized controlled trials. Sleep Med Rev. 2017;31:70–8.

    Article  PubMed  Google Scholar 

  135. Huang ZL, Urade Y, Hayaishi O. Prostaglandins and adenosine in the regulation of sleep and wakefulness. Curr Opin Pharmacol. 2007;7:33–8.

    Article  PubMed  CAS  Google Scholar 

  136. Omvik S, Pallesen S, Bjorvatn B, Thayer J, Nordhus IH. Night-time thoughts in high and low worriers: reaction to caffeine-induced sleeplessness. Behav Res Ther. 2007;45:715–27.

    Article  PubMed  Google Scholar 

  137. Calamaro CJ, Mason TB, Ratcliffe SJ. Adolescents living the 24/7 lifestyle: effects of caffeine and technology on sleep duration and daytime functioning. Pediatrics. 2009;123:e1005–10.

    Article  PubMed  Google Scholar 

  138. Shilo L, Sabbah H, Hadari R, Kovatz S, Weinberg U, Dolev S, et al. The effects of coffee consumption on sleep and melatonin secretion. Sleep Med. 2002;3:271–3.

    Article  PubMed  Google Scholar 

  139. Drake CL, Jefferson C, Roehrs T, Roth T. Stress-related sleep disturbance and polysomnographic response to caffeine. Sleep Med. 2006;7:567–72.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Paterson LM, Wilson SJ, Nutt DJ, Hutson PH, Ivarsson M. A translational, caffeine-induced model of onset insomnia in rats and healthy volunteers. Psychopharmacology (Berl). 2007;191:943–50.

    Article  PubMed  CAS  Google Scholar 

  141. Paterson LM, Wilson SJ, Nutt DJ, Hutson PH, Ivarsson M. Characterisation of the effects of caffeine on sleep in the rat: A potential model of sleep disruption. J Psychopharmacol. 2009;23:475–86.

    Article  PubMed  CAS  Google Scholar 

  142. Huang ZL, Qu WM, Eguchi N, Chen JF, Schwarzschild MA, Fredholm BB, et al. Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nat Neurosci. 2005;8:858–9.

    Article  PubMed  CAS  Google Scholar 

  143. Lazarus M, Shen HY, Cherasse Y, Qu WM, Huang ZL, Bass CE, et al. Arousal effect of caffeine depends on adenosine A2A receptors in the shell of the nucleus accumbens. J Neurosci. 2011;31:10067–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Huang ZL, Mochizuki T, Qu WM, Hong ZY, Watanabe T, Urade Y, et al. Altered sleep-wake characteristics and lack of arousal response to H3 receptor antagonist in histamine H1 receptor knockout mice. Proc Natl Acad Sci USA. 2006;103:4687–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Scammell TE, Jackson AC, Franks NP, Wisden W, Dauvilliers Y. Histamine: Neural circuits and new medications. Sleep. 2019;42:zsy183.

    Article  PubMed  Google Scholar 

  146. Takahashi K, Lin JS, Sakai K. Neuronal activity of histaminergic tuberomammillary neurons during wake-sleep states in the mouse. J Neurosci. 2006;26:10292–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Chu M, Huang ZL, Qu WM, Eguchi N, Yao MH, Urade Y. Extracellular histamine level in the frontal cortex is positively correlated with the amount of wakefulness in rats. Neurosci Res. 2004;49:417–20.

    Article  PubMed  CAS  Google Scholar 

  148. Fujita A, Bonnavion P, Wilson MH, Mickelsen LE, Bloit J, de Lecea L, et al. Hypothalamic tuberomammillary nucleus neurons: electrophysiological diversity and essential role in arousal stability. J Neurosci. 2017;37:9574–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Yu X, Ye Z, Houston CM, Zecharia AY, Ma Y, Zhang Z, et al. Wakefulness is governed by GABA and histamine cotransmission. Neuron. 2015;87:164–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Yu X, Ma Y, Harding EC, Yustos R, Vyssotski AL, Franks NP, et al. Genetic lesioning of histamine neurons increases sleep-wake fragmentation and reveals their contribution to modafinil-induced wakefulness. Sleep. 2019;42:zsz031.

    Article  PubMed  PubMed Central  Google Scholar 

  151. Ramesh V, Thakkar MM, Strecker RE, Basheer R, McCarley RW. Wakefulness-inducing effects of histamine in the basal forebrain of freely moving rats. Behav Brain Res. 2004;152:271–8.

    Article  PubMed  CAS  Google Scholar 

  152. Lin JS, Hou Y, Sakai K, Jouvet M. Histaminergic descending inputs to the mesopontine tegmentum and their role in the control of cortical activation and wakefulness in the cat. J Neurosci. 1996;16:1523–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Wang YQ, Takata Y, Li R, Zhang Z, Zhang MQ, Urade Y, et al. Doxepin and diphenhydramine increased non-rapid eye movement sleep through blockade of histamine H1 receptors. Pharmacol Biochem Behav. 2015;129:56–64.

    Article  PubMed  CAS  Google Scholar 

  154. McLeod RL, Aslanian R, del Prado M, Duffy R, Egan RW, Kreutner W, et al. Sch 50971, an orally active histamine H3 receptor agonist, inhibits central neurogenic vascular inflammation and produces sedation in the guinea pig. J Pharmacol Exp Ther. 1998;287:43–50.

    PubMed  CAS  Google Scholar 

  155. Passani MB, Lin JS, Hancock A, Crochet S, Blandina P. The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders. Trends Pharmacol Sci. 2004;25:618–25.

    Article  PubMed  CAS  Google Scholar 

  156. Ligneau X, Perrin D, Landais L, Camelin JC, Calmels TP, Berrebi-Bertrand I. et al. Bf2.649 [1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine H3 receptor: preclinical pharmacology. J Pharmacol Exp Ther. 2007;320:365–75.

  157. Barbier AJ, Berridge C, Dugovic C, Laposky AD, Wilson SJ, Boggs J, et al. Acute wake-promoting actions of JNJ-5207852, a novel, diamine-based H3 antagonist. Br J Pharmacol. 2004;143:649–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Monti JM, Monti D. The involvement of dopamine in the modulation of sleep and waking. Sleep Med Rev. 2007;11:113–33.

    Article  PubMed  Google Scholar 

  159. Wisor JP. Dopamine and wakefulness: Pharmacology, genetics, and circuitry. Handb Exp Pharmacol. 2018;253:321–35.

    Article  Google Scholar 

  160. Dong H, Wang J, Yang YF, Shen Y, Qu WM, Huang ZL. Dorsal striatum dopamine levels fluctuate across the sleep-wake cycle and respond to salient stimuli in mice. Front Neurosci. 2019;13:242.

    Article  PubMed  PubMed Central  Google Scholar 

  161. Luo YJ, Li YD, Wang L, Yang SR, Yuan XS, Wang J, et al. Nucleus accumbens controls wakefulness by a subpopulation of neurons expressing dopamine D1 receptors. Nat Commun. 2018;9:1576.

    Article  PubMed  PubMed Central  Google Scholar 

  162. Qu WM, Xu XH, Yan MM, Wang YQ, Urade Y, Huang ZL. Essential role of dopamine D2 receptor in the maintenance of wakefulness, but not in homeostatic regulation of sleep, in mice. J Neurosci. 2010;30:4382–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Monti JM, Fernandez M, Jantos H. Sleep during acute dopamine D1 agonist SKF 38393 or D1 antagonist SCH 23390 administration in rats. Neuropsychopharmacology. 1990;3:153–62.

    PubMed  CAS  Google Scholar 

  164. Burgess CR, Tse G, Gillis L, Peever JH. Dopaminergic regulation of sleep and cataplexy in a murine model of narcolepsy. Sleep. 2010;33:1295–304.

    Article  PubMed  PubMed Central  Google Scholar 

  165. Monti JM, Hawkins M, Jantos H, D’Angelo L, Fernandez M. Biphasic effects of dopamine D2 receptor agonists on sleep and wakefulness in the rat. Psychopharmacology (Berl). 1988;95:395–400.

    Article  PubMed  CAS  Google Scholar 

  166. Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM. Dopaminergic role in stimulant-induced wakefulness. J Neurosci. 2001;21:1787–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Andersen ML, Margis R, Frey BN, Giglio LM, Kapczinski F, Tufik S. Electrophysiological correlates of sleep disturbance induced by acute and chronic administration of D-amphetamine. Brain Res. 2009;1249:162–72.

    Article  PubMed  CAS  Google Scholar 

  168. Minzenberg MJ, Carter CS. Modafinil: A review of neurochemical actions and effects on cognition. Neuropsychopharmacology. 2008;33:1477–502.

    Article  PubMed  CAS  Google Scholar 

  169. Zeitzer JM, Nishino S, Mignot E. The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions. Trends Pharmacol Sci. 2006;27:368–74.

    Article  PubMed  CAS  Google Scholar 

  170. Wisor J. Modafinil as a catecholaminergic agent: empirical evidence and unanswered questions. Front Neurol. 2013;4:139.

    Article  PubMed  PubMed Central  Google Scholar 

  171. Volkow ND, Fowler JS, Logan J, Alexoff D, Zhu W, Telang F, et al. Effects of modafinil on dopamine and dopamine transporters in the male human brain: Clinical implications. JAMA. 2009;301:1148–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Fiocchi EM, Lin YG, Aimone L, Gruner JA, Flood DG. Armodafinil promotes wakefulness and activates Fos in rat brain. Pharmacol Biochem Behav. 2009;92:549–57.

    Article  PubMed  CAS  Google Scholar 

  173. Edgar DM, Seidel WF. Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat. J Pharmacol Exp Ther. 1997;283:757–69.

    PubMed  CAS  Google Scholar 

  174. Raehal KM, Bohn LM. Mu opioid receptor regulation and opiate responsiveness. AAPS J. 2005;7:E587–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Dimsdale JE, Norman D, DeJardin D, Wallace MS. The effect of opioids on sleep architecture. J Clin Sleep Med. 2007;3:33–6.

    PubMed  Google Scholar 

  176. Shaw IR, Lavigne G, Mayer P, Choiniere M. Acute intravenous administration of morphine perturbs sleep architecture in healthy pain-free young adults: A preliminary study. Sleep. 2005;28:677–82.

    Article  PubMed  Google Scholar 

  177. Wang Q, Yue XF, Qu WM, Tan R, Zheng P, Urade Y, et al. Morphine inhibits sleep-promoting neurons in the ventrolateral preoptic area via mu receptors and induces wakefulness in rats. Neuropsychopharmacology. 2013;38:791–801.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Watson CJ, Lydic R, Baghdoyan HA. Sleep and gaba levels in the oral part of rat pontine reticular formation are decreased by local and systemic administration of morphine. Neuroscience. 2007;144:375–86.

    Article  PubMed  CAS  Google Scholar 

  179. Li YJ, Zhong F, Yu P, Han JS, Cui CL, Wu LZ. Electroacupuncture treatment normalized sleep disturbance in morphine withdrawal rats. Evid Based Complement Altern Med. 2011;2011:361054.

    Article  Google Scholar 

  180. Xiao L, Tang YL, Smith AK, Xiang YT, Sheng LX, Chi Y, et al. Nocturnal sleep architecture disturbances in early methadone treatment patients. Psychiatry Res. 2010;179:91–5.

    Article  PubMed  Google Scholar 

  181. Greco MA, Fuller PM, Jhou TC, Martin-Schild S, Zadina JE, Hu Z, et al. Opioidergic projections to sleep-active neurons in the ventrolateral preoptic nucleus. Brain Res. 2008;1245:96–107.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Cronin A, Keifer JC, Baghdoyan HA, Lydic R. Opioid inhibition of rapid eye movement sleep by a specific mu receptor agonist. Br J Anaesth. 1995;74:188–92.

    Article  PubMed  CAS  Google Scholar 

  183. Gauthier EA, Guzick SE, Brummett CM, Baghdoyan HA, Lydic R. Buprenorphine disrupts sleep and decreases adenosine concentrations in sleep-regulating brain regions of sprague dawley rat. Anesthesiology. 2011;115:743–53.

    Article  PubMed  CAS  Google Scholar 

  184. Thakkar MM, Sharma R, Sahota P. Alcohol disrupts sleep homeostasis. Alcohol. 2015;49:299–310.

    Article  PubMed  CAS  Google Scholar 

  185. Roehrs T, Roth T. Sleep, sleepiness, sleep disorders and alcohol use and abuse. Sleep Med Rev. 2001;5:287–97.

    Article  PubMed  Google Scholar 

  186. Colrain IM, Turlington S, Baker FC. Impact of alcoholism on sleep architecture and eeg power spectra in men and women. Sleep. 2009;32:1341–52.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Brower KJ, Perron BE. Prevalence and correlates of withdrawal-related insomnia among adults with alcohol dependence: Results from a national survey. Am J Addict. 2010;19:238–44.

    Article  PubMed  PubMed Central  Google Scholar 

  188. Fang T, Dong H, Xu XH, Yuan XS, Chen ZK, Chen JF, et al. Adenosine A2A receptor mediates hypnotic effects of ethanol in mice. Sci Rep. 2017;7:12678.

    Article  PubMed  PubMed Central  Google Scholar 

  189. Ehlers CL, Sanchez-Alavez M, Wills D. Effect of gabapentin on sleep and delta and theta eeg power in adult rats exposed to chronic intermittent ethanol vapor and protracted withdrawal during adolescence. Psychopharmacology (Berl). 2018;235:1783–91.

    Article  PubMed  CAS  Google Scholar 

  190. Sanchez-Alavez M, Benedict J, Wills DN, Ehlers CL. Effect of suvorexant on event-related oscillations and EEG sleep in rats exposed to chronic intermittent ethanol vapor and protracted withdrawal. Sleep. 2019;42:zsz020.

    Article  PubMed  PubMed Central  Google Scholar 

  191. Kubota T, De A, Brown RA, Simasko SM, Krueger JM. Diurnal effects of acute and chronic administration of ethanol on sleep in rats. Alcohol Clin Exp Res. 2002;26:1153–61.

    Article  PubMed  CAS  Google Scholar 

  192. Ehlers CL, Slawecki CJ. Effects of chronic ethanol exposure on sleep in rats. Alcohol. 2000;20:173–9.

    Article  PubMed  CAS  Google Scholar 

  193. Hoyer D, Jacobson LH. Orexin in sleep, addiction and more: Is the perfect insomnia drug at hand? Neuropeptides. 2013;47:477–88.

    Article  PubMed  CAS  Google Scholar 

  194. Rhyne DN, Anderson SL. Suvorexant in insomnia: efficacy, safety and place in therapy. Ther Adv Drug Saf. 2015;6:189–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Ando K, Kripke DF, Ancoli-Israel S. Delayed and advanced sleep phase symptoms. Isr J Psychiatry Relat Sci. 2002;39:11–8.

    PubMed  Google Scholar 

  196. Crowley SJ, Acebo C, Carskadon MA. Sleep, circadian rhythms, and delayed phase in adolescence. Sleep Med. 2007;8:602–12.

    Article  PubMed  Google Scholar 

  197. Kim MJ, Lee JH, Duffy JF. Circadian rhythm sleep disorders. J Clin Outcomes Manag. 2013;20:513–28.

    PubMed  PubMed Central  Google Scholar 

  198. Chang AM, Reid KJ, Gourineni R, Zee PC. Sleep timing and circadian phase in delayed sleep phase syndrome. J Biol Rhythms. 2009;24:313–21.

    Article  PubMed  PubMed Central  Google Scholar 

  199. Zhang Z, Wang HJ, Wang DR, Qu WM, Huang ZL. Red light at intensities above 10lx alters sleep-wake behavior in mice. Light-Sci Appl. 2017;6:e16231.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  200. Figueiro MG. Delayed sleep phase disorder: Clinical perspective with a focus on light therapy. Nat Sci Sleep. 2016;8:91–106.

    Article  PubMed  PubMed Central  Google Scholar 

  201. Sauvet F, Gomez-Merino D, Dorey R, Ciret S, Gallopin T, Drogou C, et al. Lengthening of the photoperiod influences sleep characteristics before and during total sleep deprivation in rat. J Sleep Res. 2019;28:e12709.

    Article  PubMed  Google Scholar 

  202. Rozov SV, Zant JC, Gurevicius K, Porkka-Heiskanen T, Panula P. Altered electroencephalographic activity associated with changes in the sleep-wakefulness cycle of C57BL/6J mice in response to a photoperiod shortening. Front Behav Neurosci. 2016;10:168.

    Article  PubMed  PubMed Central  Google Scholar 

  203. King DP, Takahashi JS. Molecular genetics of circadian rhythms in mammals. Annu Rev Neurosci. 2000;23:713–42.

    Article  PubMed  CAS  Google Scholar 

  204. Laposky A, Easton A, Dugovic C, Walisser J, Bradfield C, Turek F. Deletion of the mammalian circadian clock gene BMAL1/Mop3 alters baseline sleep architecture and the response to sleep deprivation. Sleep. 2005;28:395–409.

    Article  PubMed  Google Scholar 

  205. Brager AJ, Yang T, Ehlen JC, Simon RP, Meller R, Paul KN. Sleep is critical for remote preconditioning-induced neuroprotection. Sleep. 2016;39:2033–40.

    Article  PubMed  PubMed Central  Google Scholar 

  206. Akladious A, Azzam S, Hu Y, Feng P. BMAL1 knockdown suppresses wake and increases immobility without altering orexin A, corticotrophin-releasing hormone, or glutamate decarboxylase. CNS Neurosci Ther. 2018;24:549–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  207. Wisor JP, O’Hara BF, Terao A, Selby CP, Kilduff TS, Sancar A, et al. A role for cryptochromes in sleep regulation. BMC Neurosci. 2002;3:20.

    Article  PubMed  PubMed Central  Google Scholar 

  208. Shiromani PJ, Xu M, Winston EM, Shiromani SN, Gerashchenko D, Weaver DR. Sleep rhythmicity and homeostasis in mice with targeted disruption of mperiod genes. Am J Physiol Regul Integr Comp Physiol. 2004;287:R47–57.

    Article  PubMed  CAS  Google Scholar 

  209. Kopp C, Albrecht U, Zheng B, Tobler I. Homeostatic sleep regulation is preserved in mPer1 and mPer2 mutant mice. Eur J Neurosci. 2002;16:1099–106.

    Article  PubMed  Google Scholar 

  210. Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science. 2001;291:1040–3.

    Article  PubMed  CAS  Google Scholar 

  211. Kurien P, Hsu PK, Leon J, Wu D, McMahon T, Shi G, et al. Timeless mutation alters phase responsiveness and causes advanced sleep phase. Proc Natl Acad Sci USA. 2019;116:12045–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  212. Mishima K, Tozawa T, Satoh K, Saitoh H, Mishima Y. The 3111T/C polymorphism of hClock is associated with evening preference and delayed sleep timing in a Japanese population sample. Am J Med Genet B Neuropsychiatr Genet. 2005;133B:101–4.

    Article  PubMed  Google Scholar 

  213. Wakatsuki Y, Kudo T, Shibata S. Constant light housing during nursing causes human DSPS (delayed sleep phase syndrome) behaviour in clock-mutant mice. Eur J Neurosci. 2007;25:2413–24.

    Article  PubMed  Google Scholar 

  214. Ren S, Wang Y, Yue F, Cheng X, Dang R, Qiao Q, et al. The paraventricular thalamus is a critical thalamic area for wakefulness. Science. 2018;362:429–34.

    Article  PubMed  CAS  Google Scholar 

  215. Chen CR, Zhong YH, Jiang S, Xu W, Xiao L, Wang Z, et al. Dysfunctions of the paraventricular hypothalamic nucleus induce hypersomnia in mice. Elife. 2021;10:e69909.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  216. Pedersen NP, Ferrari L, Venner A, Wang JL, Abbott SBG, Vujovic N, et al. Supramammillary glutamate neurons are a key node of the arousal system. Nat Commun. 2017;8:1405.

    Article  PubMed  PubMed Central  Google Scholar 

  217. Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, et al. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. 2019;363:880–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  218. Yu X, Li W, Ma Y, Tossell K, Harris JJ, Harding EC, et al. GABA and glutamate neurons in the VTA regulate sleep and wakefulness. Nat Neurosci. 2019;22:106–19.

    Article  PubMed  CAS  Google Scholar 

  219. Chowdhury S, Matsubara T, Miyazaki T, Ono D, Fukatsu N, Abe M, et al. GABA neurons in the ventral tegmental area regulate non-rapid eye movement sleep in mice. Elife. 2019;8:e44928.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  220. Takata Y, Oishi Y, Zhou XZ, Hasegawa E, Takahashi K, Cherasse Y, et al. Sleep and wakefulness are controlled by ventral medial midbrain/pons GABAergic neurons in mice. J Neurosci. 2018;38:10080–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  221. Ono D, Mukai Y, Hung CJ, Chowdhury S, Sugiyama T, Yamanaka A. The mammalian circadian pacemaker regulates wakefulness via CRF neurons in the paraventricular nucleus of the hypothalamus. Sci Adv. 2020;6:eabd0384.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  222. Yuan XS, Wang L, Dong H, Qu WM, Yang SR, Cherasse Y, et al. Striatal adenosine A2A receptor neurons control active-period sleep via parvalbumin neurons in external globus pallidus. Elife. 2017;6:e29055.

    Article  PubMed  PubMed Central  Google Scholar 

  223. Baglioni C, Spiegelhalder K, Regen W, Feige B, Nissen C, Lombardo C, et al. Insomnia disorder is associated with increased amygdala reactivity to insomnia-related stimuli. Sleep. 2014;37:1907–17.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was partly supported by the National Natural Science Foundation of China (82020108014 and 32070984 to ZLH; 82071491 and 31871072 to WMQ), the STI2030-Major Project (2021ZD0203400 to ZLH), Program for Shanghai Outstanding Academic Leaders (to ZLH), Shanghai Municipal Science and Technology Major Project (2018SHZDZX01 to ZLH), Zhangjiang Lab, and Shanghai Center for Brain Science and Brain-Inspired Technology, Lingang Laboratory & National Key Laboratory of Human Factors Engineering Joint Grant (LG-TKN-202203-01).

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  1. These authors contributed equally: Ze-ka Chen, Yuan-yuan Liu

Authors and Affiliations

  1. Department of Pharmacology, School of Basic Medical Sciences; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science; Joint International Research Laboratory of Sleep; and Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Ze-ka Chen, Yuan-yuan Liu, Ji-chuan Zhou, Wei-min Qu & Zhi-li Huang

  2. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Ze-ka Chen

  3. Department of Neurology (Sleep Disorders), the Affiliated Chaohu Hospital of Anhui Medical University, Hefei, 238000, China

    Gui-hai Chen

  4. Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China

    Chun-feng Liu

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  1. Ze-ka Chen
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Correspondence to Chun-feng Liu, Wei-min Qu or Zhi-li Huang.

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Chen, Zk., Liu, Yy., Zhou, Jc. et al. Insomnia-related rodent models in drug discovery. Acta Pharmacol Sin 45, 1777–1792 (2024). https://doi.org/10.1038/s41401-024-01269-w

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