Amyloid-β induces sleep fragmentation that is rescued by fatty acid binding proteins in Drosophila

Journal of Neuroscience Research

Volumn 95, Issue 8, 2017, Pages 1548-1564

  Gerstner, Jason R ^a,b   Lenz, Olivia ^a   Vanderheyden, William M ^b   Chan, May T ^a   Pfeiffenberger, Cory ^a   Pack, Allan I ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b WASHINGTON STATE UNIVERSITY   (United States)

Author keywords

amyloid ; fruit fly; neurodegeneration

Indexed keywords

AMYLOID BETA PROTEIN[1-42]; DROSOPHILA PROTEIN; FATTY ACID BINDING PROTEIN; MESSENGER RNA; AMYLOID BETA PROTEIN; GAL4 PROTEIN, DROSOPHILA; HORMONE ANTAGONIST; MIFEPRISTONE; TRANSCRIPTION FACTOR;

ADULT; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DISEASE ASSOCIATION; DROSOPHILA; GENE EXPRESSION; GENETIC MODEL; HUMAN; HYDROPHOBICITY; HYPERACTIVITY; LATENT PERIOD; LIGHT DARK CYCLE; LOCOMOTION; MALE; NIGHT SLEEP; NONHUMAN; PRIORITY JOURNAL; QUANTITATIVE ANALYSIS; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SLEEP DISORDER; SLEEP FRAGMENTATION; TRANSGENE; WAKEFULNESS; ANIMAL; CHEMICALLY INDUCED; DISEASE MODEL; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; PATHOPHYSIOLOGY; SLEEP; TRANSGENIC ANIMAL;

AMYLOID BETA-PEPTIDES; ANIMALS; ANIMALS, GENETICALLY MODIFIED; DISEASE MODELS, ANIMAL; DROSOPHILA; DROSOPHILA PROTEINS; FATTY ACID-BINDING PROTEINS; GENE EXPRESSION REGULATION; HORMONE ANTAGONISTS; HUMANS; LOCOMOTION; MIFEPRISTONE; RNA, MESSENGER; SLEEP; SLEEP WAKE DISORDERS; TRANSCRIPTION FACTORS; WAKEFULNESS;

EID: 84977118613     PISSN: 03604012     EISSN: 10974547     Source Type: Journal    
DOI: 10.1002/jnr.23778     Document Type: Article

References (90)

1. Abel T, Havekes R, Saletin JM, Walker MP. 2013. Sleep, plasticity, and memory from molecules to whole-brain networks. Curr Biol 23:R774–R788.
2. Bateman RJ, Wen G, Morris JC, Holtzman DM. 2007. Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker. Neurology 68:666–669.
3. Bennaars-Eiden A, Higgins L, Hertzel AV, Kapphahn RJ, Ferrington DA, Bernlohr DA. 2002. Covalent modification of epithelial fatty acid-binding protein by 4-hydroxynonenal in vitro and in vivo. Evidence for a role in antioxidant biology. J Biol Chem 277:50693–50702.
4. Bilen J, Bonini NM. 2005. Drosophila as a model for human neurodegenerative disease. Annu Rev Genet 39:153–171.
5. Boudrault C, Bazinet RP, Ma DW. 2009. Experimental models and mechanisms underlying the protective effects of n-3 polyunsaturated fatty acids in Alzheimer's disease. J Nutr Biochem 20:1–10.
6. Bushey D, Hughes KA, Tononi G, Cirelli C. 2010. Sleep, aging, and lifespan in Drosophila. BMC Neurosci 11:56.
7. Butterfield DA, Lauderback CM. 2002. Lipid peroxidation and protein oxidation in Alzheimer's disease brain: potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress. Free Radic Biol Med 32:1050–1060.
8. Calon F, Cole G. 2007. Neuroprotective action of omega-3 polyunsaturated fatty acids against neurodegenerative diseases: evidence from animal studies. Prostaglandins Leukotr Essent Fatty Acids 77:287–293.
9. Ceriani MF, Hogenesch JB, Yanovsky M, Panda S, Straume M, Kay SA. 2002. Genome-wide expression analysis in Drosophila reveals genes controlling circadian behavior. J Neurosci 22:9305–9319.
10. Chen KF, Possidente B, Lomas DA, Crowther DC. 2014. The central molecular clock is robust in the face of behavioural arrhythmia in a Drosophila model of Alzheimer's disease. Dis Model Mech 7:445–458.
11. Cheon MS, Kim SH, Fountoulakis M, Lubec G. 2003. Heart type fatty acid binding protein (H-FABP) is decreased in brains of patients with Down syndrome and Alzheimer's disease. J Neural Transm Suppl:225–234.
12. Chiasserini D, Parnetti L, Andreasson U, Zetterberg H, Giannandrea D, Calabresi P, Blennow K. 2010. CSF levels of heart fatty acid binding protein are altered during early phases of Alzheimer's disease. J Alzheimers Dis 22:1281–1288.
13. Cirelli C, Bushey D. 2008. Sleep and wakefulness in Drosophila melanogaster. Ann N Y Acad Sci 1129:323–329.
14. Desikan RS, Thompson WK, Holland D, Hess CP, Brewer JB, Zetterberg H, Blennow K, Andreassen OA, McEvoy LK, Hyman BT, Dale AM. 2013. Heart fatty acid binding protein and Aβ-associated Alzheimer's neurodegeneration. Mol Neurodegen 8:39.
15. Di Meco A, Joshi YB, Pratico D. 2014. Sleep deprivation impairs memory, tau metabolism, and synaptic integrity of a mouse model of Alzheimer's disease with plaques and tangles. Neurobiol Aging 35:1813–1820.
16. Dissel S, Angadi V, Kirszenblat L, Suzuki Y, Donlea J, Klose M, Koch Z, English D, Winsky-Sommerer R, van Swinderen B, Shaw PJ. 2015. Sleep restores behavioral plasticity to Drosophila mutants. Curr Biol 25:1270–1281.
17. Dyall SC. 2010. Amyloid-beta peptide, oxidative stress, and inflammation in Alzheimer's disease: potential neuroprotective effects of omega-3 polyunsaturated fatty acids. Int J Alzheimers Dis 2010:10.
18. Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR, LaRossa GN, Spinner ML, Klunk WE, Mathis CA, DeKosky ST, Morris JC, Holtzman DM. 2006. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol 59:512–519.
19. Finelli A, Kelkar A, Song HJ, Yang H, Konsolaki M. 2004. A model for studying Alzheimer's Abeta42-induced toxicity in Drosophila melanogaster. Mol Cell Neurosci 26:365–375.
20. Forsberg A, Engler H, Almkvist O, Blomquist G, Hagman G, Wall A, Ringheim A, Langstrom B, Nordberg A. 2008. PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging 29:1456–1465.
21. Ganguly-Fitzgerald I, Donlea J, Shaw PJ. 2006. Waking experience affects sleep need in Drosophila. Science 313:1775–1781.
22. Gerstner JR, Vander Heyden WM, Lavaute TM, Landry CF. 2006. Profiles of novel diurnally regulated genes in mouse hypothalamus: expression analysis of the cysteine and histidine-rich domain-containing, zinc-binding protein 1, the fatty acid-binding protein 7, and the GTPase, ras-like family member 11b. Neuroscience 139:1435–1448.
23. Gerstner JR, Bremer QZ, Vander Heyden WM, Lavaute TM, Yin JC, Landry CF. 2008. Brain fatty acid binding protein (Fabp7) is diurnally regulated in astrocytes and hippocampal granule cell precursors in adult rodent brain. PLoS One 3:e1631.
24. Gerstner JR, Vanderheyden WM, Shaw PJ, Landry CF, Yin JC. 2011a. Cytoplasmic to nuclear localization of fatty-acid binding protein correlates with specific forms of long-term memory in Drosophila. Commun Integr Biol 4:623–626.
25. Gerstner JR, Vanderheyden WM, Shaw PJ, Landry CF, Yin JC. 2011b. Fatty-acid binding proteins modulate sleep and enhance long-term memory consolidation in Drosophila. PLoS One 6:e15890.
26. Gerstner JR, Perron IJ, Pack AI. 2012a. The nexus of Aβ, aging, and sleep. Sci Transl Med 4:150fs134.
27. Gerstner JR, Vanderheyden WM, LaVaute T, Westmark CJ, Rouhana L, Pack AI, Wickens M, Landry CF. 2012b. Time of day regulates subcellular trafficking, tripartite synaptic localization, and polyadenylation of the astrocytic Fabp7 mRNA. J Neurosci 32:1383–1394.
28. Goel N, Basner M, Rao H, Dinges DF. 2013. Circadian rhythms, sleep deprivation, and human performance. Prog Mol Biol Transl Sci 119:155–190.
29. Graves L, Pack A, Abel T. 2001. Sleep and memory: a molecular perspective. Trends Neurosci 24:237–243.
30. Grimmer T, Riemenschneider M, Forstl H, Henriksen G, Klunk WE, Mathis CA, Shiga T, Wester HJ, Kurz A, Drzezga A. 2009. Beta-amyloid in Alzheimer's disease: increased deposition in brain is reflected in reduced concentration in cerebrospinal fluid. Biol Psychiatry 65:927–934.
31. Guo LH, Alexopoulos P, Perneczky R. 2013. Heart-type fatty acid binding protein and vascular endothelial growth factor: cerebrospinal fluid biomarker candidates for Alzheimer's disease. Eur Arch Psychiatry Clin Neurosci 263:553–560.
32. Haass C, Selkoe DJ. 2007. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid-beta peptide. Nat Rev Mol Cell Biol 8:101–112.
33. Hellberg K, Grimsrud PA, Kruse AC, Banaszak LJ, Ohlendorf DH, Bernlohr DA. 2010. X-ray crystallographic analysis of adipocyte fatty acid binding protein (aP2) modified with 4-hydroxy-2-nonenal. Protein Sci 19:1480–1489.
34. Ho KS, Sehgal A. 2005. Drosophila melanogaster: an insect model for fundamental studies of sleep. Methods Enzymol 393:772–793.
35. Holtzman DM, Goate A, Kelly J, Sperling R. 2011a. Mapping the road forward in Alzheimer's disease. Sci Transl Med 3:114ps48.
36. Holtzman DM, Morris JC, Goate AM. 2011b. Alzheimer's disease: the challenge of the second century. Sci Transl Med 3:77sr71.
37. Hu WT, Chen-Plotkin A, Arnold SE, Grossman M, Clark CM, Shaw LM, Pickering E, Kuhn M, Chen Y, McCluskey L, Elman L, Karlawish J, Hurtig HI, Siderowf A, Lee VM, Soares H, Trojanowski JQ. 2010. Novel CSF biomarkers for Alzheimer's disease and mild cognitive impairment. Acta Neuropathol 119:669–678.
38. Huang Y, Potter R, Sigurdson W, Santacruz A, Shih S, Ju YE, Kasten T, Morris JC, Mintun M, Duntley S, Bateman RJ. 2012. Effects of age and amyloid deposition on Aβ dynamics in the human central nervous system. Arch Neurol 69:51–58.
39. Iijima K, Liu HP, Chiang AS, Hearn SA, Konsolaki M, Zhong Y. 2004. Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer's disease. Proc Natl Acad Sci U S A 101:6623–6628.
40. Iijima-Ando K, Iijima K. 2010. Transgenic Drosophila models of Alzheimer's disease and tauopathies. Brain Struct Funct 214:245–262.
41. Ju YE, McLeland JS, Toedebusch CD, Xiong C, Fagan AM, Duntley SP, Morris JC, Holtzman DM. 2013. Sleep quality and preclinical Alzheimer disease. JAMA Neurol 70:587–593.
42. Ju YE, Lucey BP, Holtzman DM. 2014. Sleep and Alzheimer disease pathology—a bidirectional relationship. Nat Rev Neurol 10:115–119.
43. Jyoti A, Plano A, Riedel G, Platt B. 2010. EEG, activity, and sleep architecture in a transgenic AbetaPPswe/PSEN1A246E Alzheimer's disease mouse. J Alzheimers Dis 22:873–887.
44. Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. 2009. Amyloid-beta dynamics are regulated by orexin and the sleep–wake cycle. Science 326:1005–1007.
45. Kittelberger KA, Piazza F, Tesco G, Reijmers LG. 2012. Natural amyloid-beta oligomers acutely impair the formation of a contextual fear memory in mice. PLoS One 7:e29940.
46. Koh K, Evans JM, Hendricks JC, Sehgal A. 2006. A Drosophila model for age-associated changes in sleep:wake cycles. Proc Natl Acad Sci U S A 103:13843–13847.
47. Koudounas S, Green EW, Clancy D. 2012. Reliability and variability of sleep and activity as biomarkers of ageing in Drosophila. Biogerontology 13:489–499.
48. Lee SH, Lee SK, Paik D, Min KJ. 2012. Overexpression of fatty-acid-beta-oxidation-related genes extends the lifespan of Drosophila melanogaster. Oxid Med Cell Longev 2012:854502.
49. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH. 2006. A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440:352–357.
50. Lesne SE, Sherman MA, Grant M, Kuskowski M, Schneider JA, Bennett DA, Ashe KH. 2013. Brain amyloid-beta oligomers in ageing and Alzheimer's disease. Brain 136:1383–1398.
51. Liguori C, Romigi A, Nuccetelli M, Zannino S, Sancesario G, Martorana A, Albanese M, Mercuri NB, Izzi F, Bernardini S, Nitti A, Sancesario GM, Sica F, Marciani MG, Placidi F. 2014. Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. JAMA Neurol 71:1498–1505.
52. Lim MM, Gerstner JR, Holtzman DM. 2014. The sleep–wake cycle and Alzheimer's disease: what do we know? Neurodegener Dis Manag 4:351–362.
53. Lu B, Vogel H. 2009. Drosophila models of neurodegenerative diseases. Annu Rev Pathol 4:315–342.
54. Mander BA, Marks SM, Vogel JW, Rao V, Lu B, Saletin JM, Ancoli-Israel S, Jagust WJ, Walker MP. 2015. β-Amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nat Neurosci 18:1051–1057.
55. Mandrekar-Colucci S, Karlo JC, Landreth GE. 2012. Mechanisms underlying the rapid peroxisome proliferator-activated receptor-gamma-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease. J Neurosci 32:10117–10128.
56. McDermott CM, LaHoste GJ, Chen C, Musto A, Bazan NG, Magee JC. 2003. Sleep deprivation causes behavioral, synaptic, and membrane excitability alterations in hippocampal neurons. J Neurosci 23:9687–9695.
57. Menkes-Caspi N, Yamin HG, Kellner V, Spires-Jones TL, Cohen D, Stern EA. 2015. Pathological tau disrupts ongoing network activity. Neuron 85:959–966.
58. Mita R, Beaulieu MJ, Field C, Godbout R. 2010. Brain fatty acid-binding protein and omega-3/omega-6 fatty acids: mechanistic insight into malignant glioma cell migration. J Biol Chem 285:37005–37015.
59. Nicholson L, Singh GK, Osterwalder T, Roman GW, Davis RL, Keshishian H. 2008. Spatial and temporal control of gene expression in Drosophila using the inducible GeneSwitch GAL4 system. I. Screen for larval nervous system drivers. Genetics 178:215–234.
60. O'Bryant SE, Xiao G, Edwards M, Devous M, Gupta VB, Martins R, Zhang F, Barber R. 2013. Biomarkers of Alzheimer's disease among Mexican Americans. J Alzheimers Dis 34:841–849.
61. Ohrfelt A, Andreasson U, Simon A, Zetterberg H, Edman A, Potter W, Holder D, Devanarayan V, Seeburger J, Smith AD, Blennow K, Wallin A. 2011. Screening for new biomarkers for subcortical vascular dementia and Alzheimer's disease. Dement Geriatr Cogn Dis Extra 1:31–42.
62. Olsson B, Hertze J, Ohlsson M, Nagga K, Hoglund K, Basun H, Annas P, Lannfelt L, Andreasen N, Minthon L, Zetterberg H, Blennow K, Hansson O. 2013. Cerebrospinal fluid levels of heart fatty acid binding protein are elevated prodromally in Alzheimer's disease and vascular dementia. J Alzheimers Dis 34:673–679.
63. Osorio RS, Pirraglia E, Aguera-Ortiz LF, During EH, Sacks H, Ayappa I, Walsleben J, Mooney A, Hussain A, Glodzik L, Frangione B, Martinez-Martin P, de Leon MJ. 2011. Greater risk of Alzheimer's disease in older adults with insomnia. J Am Geriatr Soc 59:559–562.
64. Osorio RS, Gumb T, Pirraglia E, Varga AW, Lu SE, Lim J, Wohlleber ME, Ducca EL, Koushyk V, Glodzik L, Mosconi L, Ayappa I, Rapoport DM, de Leon MJ. 2015. Sleep-disordered breathing advances cognitive decline in the elderly. Neurology 84:1964–1971.
65. Osterwalder T, Yoon KS, White BH, Keshishian H. 2001. A conditional tissue-specific transgene expression system using inducible GAL4. Proc Natl Acad Sci U S A 98:12596–12601.
66. Panda S, Antoch MP, Miller BH, Su AI, Schook AB, Straume M, Schultz PG, Kay SA, Takahashi JS, Hogenesch JB. 2002. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109:307–320.
67. Pitman JL, McGill JJ, Keegan KP, Allada R. 2006. A dynamic role for the mushroom bodies in promoting sleep in Drosophila. Nature 441:753–756.
68. Pollak CP, Perlick D. 1991. Sleep problems and institutionalization of the elderly. J Geriatr Psychiatry Neurol 4:204–210.
69. Prinz PN, Vitaliano PP, Vitiello MV, Bokan J, Raskind M, Peskind E, Gerber C. 1982. Sleep, EEG, and mental function changes in senile dementia of the Alzheimer's type. Neurobiol Aging 3:361–370.
70. Rogers I, Kerr F, Martinez P, Hardy J, Lovestone S, Partridge L. 2012. Ageing increases vulnerability to aβ42 toxicity in Drosophila. PLoS One 7:e40569.
71. Roh JH, Huang Y, Bero AW, Kasten T, Stewart FR, Bateman RJ, Holtzman DM. 2012. Disruption of the sleep–wake cycle and diurnal fluctuation of beta-amyloid in mice with Alzheimer's disease pathology. Sci Transl Med 4:150ra122.
72. Roman G, Endo K, Zong L, Davis RL. 2001. P[Switch], a system for spatial and temporal control of gene expression in Drosophila melanogaster. Proc Natl Acad Sci U S A 98:12602–12607.
73. Rothman SM, Herdener N, Frankola KA, Mughal MR, Mattson MP. 2013. Chronic mild sleep restriction accentuates contextual memory impairments and accumulations of cortical Aβ and pTau in a mouse model of Alzheimer's disease. Brain Res 1529:200–208.
74. Sheline YI, Raichle ME, Snyder AZ, Morris JC, Head D, Wang S, Mintun MA. 2010. Amyloid plaques disrupt resting state default mode network connectivity in cognitively normal elderly. Biol Psychiatry 67:584–587.
75. Sperling RA, Laviolette PS, O'Keefe K, O'Brien J, Rentz DM, Pihlajamaki M, Marshall G, Hyman BT, Selkoe DJ, Hedden T, Buckner RL, Becker JA, Johnson KA. 2009. Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron 63:178–188.
76. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH. 2011. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 7:280–292.
77. Spira AP, Gamaldo AA, An Y, Wu MN, Simonsick EM, Bilgel M, Zhou Y, Wong DF, Ferrucci L, Resnick SM. 2013. Self-reported sleep and beta-amyloid deposition in community-dwelling older adults. JAMA Neurol 70:1537–1543.
78. Sprecher KE, Bendlin BB, Racine AM, Okonkwo OC, Christian BT, Koscik RL, Sager MA, Asthana S, Johnson SC, Benca RM. 2015. Amyloid burden is associated with self-reported sleep in nondemented late middle-aged adults. Neurobiol Aging 36:2568–2576.
79. Tabuchi M, Lone SR, Liu S, Liu Q, Zhang J, Spira AP, Wu MN. 2015. Sleep interacts with aβ to modulate intrinsic neuronal excitability. Curr Biol 25:702–712.
80. Teunissen CE, Veerhuis R, De Vente J, Verhey FR, Vreeling F, van Boxtel MP, Glatz JF, Pelsers MA. 2011. Brain-specific fatty acid-binding protein is elevated in serum of patients with dementia-related diseases. Eur J Neurol 18:865–871.
81. Vanderheyden WM, Gerstner JR, Tanenhaus A, Yin JC, Shaw PJ. 2013. ERK phosphorylation regulates sleep and plasticity in Drosophila. PLoS One 8:e81554.
82. Vitiello MV, Borson S. 2001. Sleep disturbances in patients with Alzheimer's disease: epidemiology, pathophysiology, and treatment. CNS Drugs 15:777–796.
83. Weldemichael DA, Grossberg GT. 2010. Circadian rhythm disturbances in patients with Alzheimer's disease: a review. Int J Alzheimers Dis 2010.
84. Wisor JP, Edgar DM, Yesavage J, Ryan HS, McCormick CM, Lapustea N, Murphy GM Jr. 2005. Sleep and circadian abnormalities in a transgenic mouse model of Alzheimer's disease: a role for cholinergic transmission. Neuroscience 131:375–385.
85. Wu YH, Swaab DF. 2007. Disturbance and strategies for reactivation of the circadian rhythm system in aging and Alzheimer's disease. Sleep Med 8:623–636.
86. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. 2013. Sleep drives metabolite clearance from the adult brain. Science 342:373–377.
87. Xu LZ, Sanchez R, Sali A, Heintz N. 1996. Ligand specificity of brain lipid-binding protein. J Biol Chem 271:24711–24719.
88. Yamanaka M, Ishikawa T, Griep A, Axt D, Kummer MP, Heneka MT. 2012. PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J Neurosci 32:17321–17331.
89. Zhang B, Veasey SC, Wood MA, Leng LZ, Kaminski C, Leight S, Abel T, Lee VM, Trojanowski JQ. 2005. Impaired rapid eye movement sleep in the Tg2576 APP murine model of Alzheimer's disease with injury to pedunculopontine cholinergic neurons. Am J Pathol 167:1361–1369.
90. Zimmerman JE, Raizen DM, Maycock MH, Maislin G, Pack AI. 2008. A video method to study Drosophila sleep. Sleep 31:1587–1598.