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Acta Neuropathologica

, Volume 130, Issue 2, pp 185–198 | Cite as

Decreased orexin (hypocretin) immunoreactivity in the hypothalamus and pontine nuclei in sudden infant death syndrome

  • Nicholas J. Hunt
  • Karen A. Waters
  • Michael L. Rodriguez
  • Rita Machaalani
Original Paper

Abstract

Infants at risk of sudden infant death syndrome (SIDS) have been shown to have dysfunctional sleep and poor arousal thresholds. In animal studies, both these attributes have been linked to impaired signalling of the neuropeptide orexin. This study examined the immunoreactivity of orexin (OxA and OxB) in the tuberal hypothalamus (n = 27) and the pons (n = 15) of infants (1–10 months) who died from SIDS compared to age-matched non-SIDS infants. The percentage of orexin immunoreactive neurons and the total number of neurons were quantified in the dorsomedial, perifornical and lateral hypothalamus at three levels of the tuberal hypothalamus. In the pons, the area of orexin immunoreactive fibres were quantified in the locus coeruleus (LC), dorsal raphe (DR), laterodorsal tegmental (LDT), medial parabrachial, dorsal tegmental (DTg) and pontine nuclei (Pn) using automated methods. OxA and OxB were co-expressed in all hypothalamic and pontine nuclei examined. In SIDS infants, orexin immunoreactivity was decreased by up to 21 % within each of the three levels of the hypothalamus compared to non-SIDS (p ≤ 0.050). In the pons, a 40–50 % decrease in OxA occurred in the all pontine nuclei, while a similar decrease in OxB immunoreactivity was observed in the LC, LDT, DTg and Pn (p ≤ 0.025). No correlations were found between the decreased orexin immunoreactivity and previously identified risk factors for SIDS, including prone sleeping position and cigarette smoke exposure. This finding of reduced orexin immunoreactivity in SIDS infants may be associated with sleep dysfunction and impaired arousal.

Keywords

Human SIDS Development Sleep Sleep dysfunction REM Automated fibre quantification 

Abbreviations

DMH

Dorsomedial hypothalamus

DR

Dorsal raphe

DTg

Dorsal tegmental nucleus

LH

Lateral hypothalamus

LDT

Laterodorsal tegmental nucleus

LC

Locus coeruleus

MPB

Medial parabrachial nucleus

Ox

Orexin

OxA

Orexin A

OxB

Orexin B

PPT

Pedunculopontine tegmental area

PeF

Perifornical area

Pn

Pontine nucleus

PPO

Prepro-orexin

REM

Rapid eye movement

URTIs

Upper respiratory tract infections

Notes

Acknowledgments

The tissue used in this study was provided by the NSW Forensic and Analytical Science Service. The authors acknowledge the facilities, and scientific and technical assistance of the Australian Microscopy and Microanalysis Research Faculty at the Australian Centre of Microscopy and Micro Analysis, University of Sydney. Research funded by the SIDS Stampede, Australia, and the Miranda Bradshaw Foundation.

Conflict of interest

The authors report no conflicts of interest.

Supplementary material

401_2015_1437_MOESM1_ESM.docx (3.8 mb)
Supplementary material 1 (DOCX 3883 kb)

References

  1. 1.
    Alexandre C, Andermann ML, Scammell TE (2013) Control of arousal by the orexin neurons. Curr Opin Neurobiol 23:752–759PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Balkowiec A, Katz DM (1998) Brain-derived neurotrophic factor is required for normal development of the central respiratory rhythm in mice. J Physiol 510:527–533PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Blumberg MS, Coleman CM, Johnson ED, Shaw C (2007) Developmental divergence of sleep-wake patterns in orexin knockout and wild-type mice. Eur J Neurosci 25:512–518PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Bochorishvili G, Nguyen T, Coates MB, Viar KE, Stornetta RL, Guyenet PG (2014) The orexinergic neurons receive synaptic input from C1 cells in rats. J Comp Neurol 522:3834–3846PubMedCrossRefGoogle Scholar
  5. 5.
    Brischoux F, Mainville L, Jones BE (2008) Muscarinic-2 and orexin-2 receptors on GABAergic and other neurons in the rat mesopontine tegmentum and their potential role in sleep–wake state control. J Comp Neurol 510:607–630PubMedCrossRefGoogle Scholar
  6. 6.
    Broughton R, Krupa S, Boucher B, Rivers M, Mullington J (1997) Impaired circadian waking arousal in narcolepsy-cataplexy. SRO 1:159–165Google Scholar
  7. 7.
    Brownell SE, Conti B (2010) Age-and gender-specific changes of hypocretin immunopositive neurons in C57Bl/6 mice. Neurosci Lett 472:29–32PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Burke PG, Abbott SB, Coates MB, Viar KE, Stornetta RL, Guyenet PG (2014) Optogenetic stimulation of adrenergic C1 neurons causes sleep state dependent cardiorespiratory stimulation and arousal with sighs in rats. Am J Respir Crit Care Med 190(11):1301–1310PubMedCrossRefGoogle Scholar
  9. 9.
    Carter ME, de Lecea L, Adamantidis A (2013) Functional wiring of hypocretin and LC-NE neurons: implications for arousal. Front Behav Neurosci 7:43. doi: 10.3389/fnbeh.2013.00043 PubMedCentralPubMedGoogle Scholar
  10. 10.
    Carter ME, Yizhar O, Chikahisa S, Nguyen H, Adamantidis A, Nishino S, Deisseroth K, de Lecea L (2010) Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat Neurosci 13:1526–1533PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98:437–451PubMedCrossRefGoogle Scholar
  12. 12.
    Chen L, McKenna JT, Bolortuya Y, Brown RE, McCarley RW (2013) Knockdown of orexin type 2 receptor in the lateral pontomesencephalic tegmentum of rats increases REM sleep. Eur J Neurosci 37:957–963PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Chen L, McKenna JT, Bolortuya Y, Winston S, Thakkar MM, Basheer R, Brown RE, McCarley RW (2010) Knockdown of orexin type 1 receptor in rat locus coeruleus increases REM sleep during the dark period. Eur J Neurosci 32:1528–1536PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Chen L, Thakkar MM, Winston S, Bolortuya Y, Basheer R, McCarley RW (2006) REM sleep changes in rats induced by siRNA-mediated orexin knockdown. Eur J Neurosci 24:2039–2048PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Chiodini BA, Thach BT (1993) Impaired ventilation in infants sleeping facedown: potential significance for sudden infant death syndrome. J Pediatr 123:686–692PubMedCrossRefGoogle Scholar
  16. 16.
    Cornwell AC (1993) Sex differences in the maturation of sleep/wake patterns in high risk for SIDS infants. Neuropediatrics 24:8–14PubMedCrossRefGoogle Scholar
  17. 17.
    Cornwell AC, Feigenbaum P (2006) Sleep biological rhythms in normal infants and those at high risk for SIDS. Chronobiol Int 23:935–961PubMedCrossRefGoogle Scholar
  18. 18.
    Cornwell AC, Feigenbaum P, Kim A (1998) SIDS, abnormal nighttime REM sleep and CNS immaturity. Neuropediatrics 29:72–79PubMedCrossRefGoogle Scholar
  19. 19.
    Crocker A, España RA, Papadopoulou M, Saper CB, Faraco J, Sakurai T, Honda M, Mignot E, Scammell TE (2005) Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. Neurology 65:1184–1188PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Darnall RA, Harris MB, Gill WH, Hoffman JM, Brown JW, Niblock MM (2005) Inhibition of serotonergic neurons in the nucleus paragigantocellularis lateralis fragments sleep and decreases rapid eye movement sleep in the piglet: implications for sudden infant death syndrome. J Neurosci 25:8322–8332PubMedCrossRefGoogle Scholar
  21. 21.
    De Lecea L, Kilduff T, Peyron C, Gao X-B, Foye P, Danielson P, Fukuhara C, Battenberg E, Gautvik V, Bartlett F (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci 95:322–327PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Deurveilher S, Lo H, Murphy JA, Burns J, Semba K (2006) Differential c-Fos immunoreactivity in arousal-promoting cell groups following systemic administration of caffeine in rats. J Comp Neurol 498:667–689. doi: 10.1002/cne.21084 PubMedCrossRefGoogle Scholar
  23. 23.
    Dias MB, Li A, Nattie E (2010) The orexin receptor 1 (OX 1R) in the rostral medullary raphe contributes to the hypercapnic chemoreflex in wakefulness, during the active period of the diurnal cycle. Respir Physiol Neurobiol 170:96–102PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Dias MB, Li A, Nattie EE (2009) Antagonism of orexin receptor-1 in the retrotrapezoid nucleus inhibits the ventilatory response to hypercapnia predominantly in wakefulness. J Physiol 587:2059–2067PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Downs JL, Dunn MR, Borok E, Shanabrough M, Horvath TL, Kohama SG, Urbanski HF (2007) Orexin neuronal changes in the locus coeruleus of the aging rhesus macaque. Neurobiol Aging 28:1286–1295PubMedCrossRefGoogle Scholar
  26. 26.
    Du MK, Hunt NJ, Waters KA, Machaalani R (2014) Orexin/hypocretin neuropeptides in the developing piglet hypothalamus after increasing duration of intermittent hypercapnic hypoxia. In: Poster presented at the Australasian Neuroscience Society Annal General Meeting, Adelaide. Abstract retrieved from: http://www.aomeventscom/media/files/ANS/WED%20POSTER%20PROCEEDINGS%20for%20website.pdf
  27. 27.
    Duncan JR, Paterson DS, Hoffman JM, Mokler DJ, Borenstein NS, Belliveau RA, Krous HF, Haas EA, Stanley C, Nattie EE (2010) Brainstem serotonergic deficiency in sudden infant death syndrome. JAMA 303:430–437PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Krous HF (2010) Sudden unexpected death in infancy and the dilemma of defining the sudden infant death syndrome. Curr Pediatr Rev 6:5–12CrossRefGoogle Scholar
  29. 29.
    Fronczek R, Overeem S, Lee SY, Hegeman IM, van Pelt J, van Duinen SG, Lammers GJ, Swaab DF (2007) Hypocretin (orexin) loss in Parkinson’s disease. Brain 130:1577–1585PubMedCrossRefGoogle Scholar
  30. 30.
    Gestreau C, Bévengut M, Dutschmann M (2008) The dual role of the orexin/hypocretin system in modulating wakefulness and respiratory drive. Curr Opin Pulm Med 14:512–518PubMedCrossRefGoogle Scholar
  31. 31.
    Glavas MM, Grayson BE, Allen SE, Copp DR, Smith MS, Cowley MA, Grove KL (2008) Characterization of brainstem peptide YY (PYY) neurons. J Comp Neurol 506:194–210PubMedCrossRefGoogle Scholar
  32. 32.
    Grider MH, Chen Q, David Shine H (2006) Semi-automated quantification of axonal densities in labeled CNS tissue. J Neurosci Methods 155:172–179PubMedCrossRefGoogle Scholar
  33. 33.
    Guilleminault C, Ariagno R, Korobkin R, Coons S, Owen-Boeddiker M, Baldwin R (1981) Sleep parameters and respiratory variables in ‘near miss’ sudden infant death syndrome infants. Pediatrics 68:354–360PubMedGoogle Scholar
  34. 34.
    Guilleminault C, Ariagno R, Souquet M, Dement W (1976) Abnormal polygraphic findings in near-miss sudden infant death. Lancet 307:1326–1327CrossRefGoogle Scholar
  35. 35.
    Guilleminault C, Peraita R, Souquet M, Dement WC (1975) Apneas during sleep in infants: possible relationship with sudden infant death syndrome. Science 190:677–679PubMedCrossRefGoogle Scholar
  36. 36.
    Guilleminault C, Souquet M, Ariagno RL, Korobkin R, Simmons FB (1984) Five cases of near-miss sudden infant death syndrome and development of obstructive sleep apnea syndrome. Pediatrics 73:71–78PubMedGoogle Scholar
  37. 37.
    Guyenet PG (2000) Neural structures that mediate sympathoexcitation during hypoxia. Respir Physiol 121:147–162PubMedCrossRefGoogle Scholar
  38. 38.
    Guyenet PG, Abbott SB (2013) Chemoreception and asphyxia-induced arousal. Respir Physiol Neurobiol 188:333–343PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Haddad GG, Walsh EM, Leistner HL, Grodin WK, Mellins RB (1981) Abnormal maturation of sleep states in infants with aborted sudden infant death syndrome. Pediatr Res 15:1055–1057PubMedCrossRefGoogle Scholar
  40. 40.
    Hagan JJ, Leslie RA, Patel S, Evans ML, Wattam TA, Holmes S, Benham CD, Taylor SG, Routledge C, Hemmati P (1999) Orexin A activates locus coeruleus cell firing and increases arousal in the rat. PNAS 96:10911–10916PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Haj-Dahmane S, Shen R-Y (2005) The wake-promoting peptide orexin-B inhibits glutamatergic transmission to dorsal raphe nucleus serotonin neurons through retrograde endocannabinoid signaling. J Neurosci 25:896–905. doi: 10.1523/jneurosci.3258-04.2005 PubMedCrossRefGoogle Scholar
  42. 42.
    Harrington C, Kirjavainen T, Teng A, Sullivan CE (2002) Altered autonomic function and reduced arousability in apparent life-threatening event infants with obstructive sleep apnea. Am J Respir Crit Care Med 165:1048–1054PubMedCrossRefGoogle Scholar
  43. 43.
    Horne RS, Ferens D, Watts A-M, Vitkovic J, Lacey B, Andrew S, Cranage SM, Chau B, Adamson TM (2001) The prone sleeping position impairs arousability in term infants. J Pediatr 138:811–816PubMedCrossRefGoogle Scholar
  44. 44.
    Hsu DT, Price JL (2009) Paraventricular thalamic nucleus: subcortical connections and innervation by serotonin, orexin, and corticotropin-releasing hormone in macaque monkeys. J Comp Neurol 512:825–848PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Hunt NJ, Rodriguez ML, Waters KA, Machaalani R (2015) Changes in orexin (hypocretin) neuronal expression with normal aging in the human hypothalamus. Neurobiol Aging 36:292–300PubMedCrossRefGoogle Scholar
  46. 46.
    Jensen LL, Banner J, Ulhøi BP, Byard RW (2014) β-Amyloid precursor protein staining of the brain in sudden infant and early childhood death. Neuropathol Appl Neurobiol 40:385–397PubMedCrossRefGoogle Scholar
  47. 47.
    Kahn A, Groswasser J, Franco P, Scaillet S, Sawaguchi T, Kelmanson I, Dan B (2003) Sudden infant deaths: stress, arousal and SIDS. Early Hum Dev 75:147–166CrossRefGoogle Scholar
  48. 48.
    Kato I, Franco P, Groswasser J, Scaillet S, Kelmanson I, Togari H, Kahn A (2003) Incomplete arousal processes in infants who were victims of sudden death. Am J Respir Crit Care Med 168:1298–1303PubMedCrossRefGoogle Scholar
  49. 49.
    Kaur S, Thankachan S, Begum S, Blanco-Centurion C, Sakurai T, Yanagisawa M, Shiromani PJ (2008) Entrainment of temperature and activity rhythms to restricted feeding in orexin knock out mice. Brain Res 1205:47–54PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Kelly DH, Shannon DC (1979) Periodic breathing in infants with near-miss sudden infant death syndrome. Pediatrics 63:355–360PubMedGoogle Scholar
  51. 51.
    Kelz MB, Sun Y, Chen J, Meng QC, Moore JT, Veasey SC, Dixon S, Thornton M, Funato H, Yanagisawa M (2008) An essential role for orexins in emergence from general anesthesia. PNAS 105:1309–1314PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Kinney HC, Filiano J, Harper RM (1992) The neuropathology of the sudden infant death syndrome. A review. J Neuropathol Exp Neurol 51:115–126PubMedCrossRefGoogle Scholar
  53. 53.
    Kinney HC, Randall LL, Sleeper LA, Willinger M, Belliveau RA, Zec N, Rava LA, Dominici L, Iyasu S, Randall B et al (2003) Serotonergic brainstem abnormalities in northern plains Indians with the sudden infant death syndrome. J Neuropathol Exp Neurol 62:1178–1191PubMedGoogle Scholar
  54. 54.
    Kinney HC, Richerson GB, Dymecki SM, Darnall RA, Nattie EE (2009) The brainstem and serotonin in the sudden infant death syndrome. Annu Rev Pathol 4:517PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Kinney HC, Thach BT (2009) The sudden infant death syndrome. N Engl J Med 361:795–805PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Kohlmeier KA, Tyler CJ, Kalogiannis M, Ishibashi M, Kristensen MP, Gumenchuk I, Chemelli RM, Kisanuki YY, Yanagisawa M, Leonard CS (2013) Differential actions of orexin receptors in brainstem cholinergic and monoaminergic neurons revealed by receptor knockouts: implications for orexinergic signaling in arousal and narcolepsy. Front Neurosci 7:246. doi: 10.3389/fnins.2013.00246 PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Kohyama JUN, Shimohira M, Itoh M, Fukumizu M, Iwakawa Y (1993) Phasic muscle activity during REM sleep in infancy—normal maturation and contrastive abnormality in SIDS/ALTE and West syndrome. J Sleep Res 2:241–249. doi: 10.1111/j.1365-2869.1993.tb00095.x PubMedCrossRefGoogle Scholar
  58. 58.
    Lavezzi AM, Matturri L (2008) Functional neuroanatomy of the human pre-Bötzinger complex with particular reference to sudden unexplained perinatal and infant death. Neuropathology 28:10–16PubMedCrossRefGoogle Scholar
  59. 59.
    Lazarenko RM, Stornetta RL, Bayliss DA, Guyenet PG (2011) Orexin A activates retrotrapezoid neurons in mice. Respir Physiol Neurobiol 175:283–287PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Liu R-J, van den Pol AN, Aghajanian GK (2002) Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J Neurosci 22:9453–9464PubMedGoogle Scholar
  61. 61.
    Liu Z, Jiang L, Zhu F, Fu C, Lu S, Zhou J, Wu X, Bai C, Li S (2014) Chronic intermittent hypoxia and the expression of orexin and its receptors in the brains of rats. Sleep Biol Rhythms 12:22–29CrossRefGoogle Scholar
  62. 62.
    Lu J, Sherman D, Devor M, Saper CB (2006) A putative flip–flop switch for control of REM sleep. Nature 441:589–594PubMedCrossRefGoogle Scholar
  63. 63.
    Machaalani R, Rodriguez M, Waters K (2007) Active caspase-3 in the sudden infant death syndrome (SIDS) brainstem. Acta Neuropathol 113:577–584PubMedCrossRefGoogle Scholar
  64. 64.
    Machaalani R, Say M, Waters KA (2009) Serotoninergic receptor 1A in the sudden infant death syndrome brainstem medulla and associations with clinical risk factors. Acta Neuropathol 117:257–265PubMedCrossRefGoogle Scholar
  65. 65.
    Machaalani R, Waters KA (2014) Neurochemical abnormalities in the brainstem of the sudden infant death syndrome (SIDS). Paediatr Respir Rev 15(4):293–300PubMedGoogle Scholar
  66. 66.
    Machaalani R, Waters KA (2008) Neuronal cell death in the sudden infant death syndrome brainstem and associations with risk factors. Brain 131:218–228PubMedCrossRefGoogle Scholar
  67. 67.
    Mai JK, Paxinos G, Voss T (2008) Atlas of the human brain. Academic Press Inc., San DiegoGoogle Scholar
  68. 68.
    Manzke T, Preusse S, Hülsmann S, Richter DW (2008) Developmental changes of serotonin 4 (a) receptor expression in the rat pre-Bötzinger complex. J Comp Neurol 506:775–790PubMedCrossRefGoogle Scholar
  69. 69.
    Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435:6–25PubMedCrossRefGoogle Scholar
  70. 70.
    Martelli D, Stanić D, Dutschmann M (2013) The emerging role of the parabrachial complex in the generation of wakefulness drive and its implication for respiratory control. Respir Physiol Neurobiol 188:318–323PubMedCrossRefGoogle Scholar
  71. 71.
    McCulloch K, Brouillette RT, Guzzetta AJ, Hunt CE (1982) Arousal responses in near-miss sudden infant death syndrome and in normal infants. J Pediatr 101:911–917PubMedCrossRefGoogle Scholar
  72. 72.
    Miano S, Castaldo R, Ferri R, Peraita-Adrados R, Paolino MC, Montesano M, Villa MP (2012) Sleep cyclic alternating pattern analysis in infants with apparent life-threatening events: a daytime polysomnographic study. Clin Neurophysiol 123:1346–1352PubMedCrossRefGoogle Scholar
  73. 73.
    Monti JM (2010) The role of dorsal raphe nucleus serotonergic and non-serotonergic neurons, and of their receptors, in regulating waking and rapid eye movement (REM) sleep. Sleep Med Rev 14:319–327PubMedCrossRefGoogle Scholar
  74. 74.
    Mosko S, Richard C, McKenna J, Drummond S (1996) Infant sleep architecture during bedsharing and possible implications for SIDS. Sleep 19:677–684PubMedGoogle Scholar
  75. 75.
    Nakamura A, Zhang W, Yanagisawa M, Fukuda Y, Kuwaki T (2007) Vigilance state-dependent attenuation of hypercapnic chemoreflex and exaggerated sleep apnea in orexin knockout mice. J Appl Physiol 102:241–248PubMedCrossRefGoogle Scholar
  76. 76.
    Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K (1999) Distribution of orexin neurons in the adult rat brain. Brain Res 827:243–260PubMedCrossRefGoogle Scholar
  77. 77.
    Obukuro K, Nobunaga M, Takigawa M, Morioka H, Hisatsune A, Isohama Y, Shimokawa H, Tsutsui M, Katsuki H (2013) Nitric oxide mediates selective degeneration of hypothalamic orexin neurons through dysfunction of protein disulfide isomerase. J Neurosci 33:12557–12568PubMedCrossRefGoogle Scholar
  78. 78.
    Obukuro K, Takigawa M, Hisatsune A, Isohama Y, Katsuki H (2010) Quinolinate induces selective loss of melanin-concentrating hormone neurons, rather than orexin neurons, in the hypothalamus of mice and young rats. J Neurosci 170:298–307CrossRefGoogle Scholar
  79. 79.
    Panigrahy A, Filiano J, Sleeper LA, Mandell F, Valdes-Dapena M, Krous HF, Rava LA, Foley E, White WF, Kinney HC (2000) Decreased serotonergic receptor binding in rhombic lip-derived regions of the medulla oblongata in the sudden infant death syndrome. J Neuropathol Exp Neurol 59:377–384PubMedGoogle Scholar
  80. 80.
    Paxino G, Huang X-F (1995) Atlas of the human brain stem. Academic Press, California CityGoogle Scholar
  81. 81.
    Randall BB, Paterson DS, Haas EA, Broadbelt KG, Duncan JR, Mena OJ, Krous HF, Trachtenberg FL, Kinney HC (2013) Potential asphyxia and brainstem abnormalities in sudden and unexpected death in infants. Pediatrics 132:e1616–e1625PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Read PA, Horne RS, Cranage SM, Walker AM, Walker DW, Adamson TM (1998) Dynamic changes in arousal threshold during sleep in the human infant. Pediatr Res 43:697–703PubMedCrossRefGoogle Scholar
  83. 83.
    Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585PubMedCrossRefGoogle Scholar
  84. 84.
    Sakurai T, Mieda M (2011) Connectomics of orexin-producing neurons: interface of systems of emotion, energy homeostasis and arousal. Trends Pharmacol Sci 32:451–462PubMedCrossRefGoogle Scholar
  85. 85.
    Sampogna S, Morales FR (2001) Orexin (hypocretin)-like immunoreactivity in the cat hypothalamus: a light and electron microscopic study. Sleep 24:67PubMedGoogle Scholar
  86. 86.
    Samson-Dollfus D, Delapierre G, Nogues B, Bertoldi I (1988) Sleep organization in children at risk for sudden infant death syndrome. Sleep 11:277–285PubMedGoogle Scholar
  87. 87.
    Sanford LD, Suchecki D, Meerlo P (2014) Stress, arousal, and sleep. Curr Top Behav Neurosci 1–32. doi: 10.1007/7854_2014_314
  88. 88.
    Sathyanesan A, Ogura T, Lin W (2012) Automated measurement of nerve fiber density using line intensity scan analysis. J Neurosci Methods 206:165–175PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Sawai N, Ueta Y, Nakazato M, Ozawa H (2010) Developmental and aging change of orexin-A and-B immunoreactive neurons in the male rat hypothalamus. Neurosci Lett 468:51–55PubMedCrossRefGoogle Scholar
  90. 90.
    Scammell TE (2003) The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 53:154–166PubMedCrossRefGoogle Scholar
  91. 91.
    Schechtman VL, Harper RM, Wilson AJ, Southall DP (1992) Sleep state organization in normal infants and victims of the sudden infant death syndrome. Pediatrics 89:865–870PubMedGoogle Scholar
  92. 92.
    Sokołowska P, Urbańska A, Biegańska K, Wagner W, Ciszewski W, Namiecińska M, Zawilska JB (2014) Orexins protect neuronal cell cultures against hypoxic stress: an involvement of Akt signaling. J Mol Neurosci 52:48–55PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Sokołowska P, Urbańska A, Namiecińska M, Biegańska K, Zawilska JB (2012) Orexins promote survival of rat cortical neurons. Neurosci Lett 506:303–306PubMedCrossRefGoogle Scholar
  94. 94.
    Sparks DL, Hunsaker JC (1991) Sudden infant death syndrome: altered aminergic-cholinergic synaptic markers in hypothalamus. J Child Neurol 6:335–339. doi: 10.1177/088307389100600409 PubMedCrossRefGoogle Scholar
  95. 95.
    Sturner W, Lynch H, Deng M, Gleason R, Wurtman R (1990) Melatonin concentrations in the sudden infant death syndrome. Forensic Sci Int 45:171–180PubMedCrossRefGoogle Scholar
  96. 96.
    Swaab D (1995) Development of the human hypothalamus. Neurochem Res 20:509–519PubMedCrossRefGoogle Scholar
  97. 97.
    Thach BT (2005) The role of respiratory control disorders in SIDS. Respir Physiol Neurobiol 149:343–353PubMedCrossRefGoogle Scholar
  98. 98.
    Thakkar MM, Ramesh V, Cape EG, Winston S, Strecker RE, McCarley RW (1998) REM sleep enhancement and behavioral cataplexy following orexin (hypocretin)-II receptor antisense perfusion in the pontine reticular formation. SRO 2:112–120Google Scholar
  99. 99.
    Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, Cornford M, Siegel JM (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27:469–474PubMedCrossRefGoogle Scholar
  100. 100.
    Thoby-Brisson M, Trinh J-B, Champagnat J, Fortin G (2005) Emergence of the pre-Bötzinger respiratory rhythm generator in the mouse embryo. J Neurosci 25:4307–4318PubMedCrossRefGoogle Scholar
  101. 101.
    Wang W, Li Q, Pan Y, Zhu D, Wang L (2013) Influence of hypercapnia on the synthesis of neuropeptides and their receptors in murine brain. Respirology 18:102–107PubMedCrossRefGoogle Scholar
  102. 102.
    Waters KA, Meehan B, Huang J, Gravel RA, Michaud J, Côté A (1999) Neuronal apoptosis in sudden infant death syndrome. Pediatr Res 45:166–172PubMedCrossRefGoogle Scholar
  103. 103.
    Williams RH, Burdakov D (2008) Hypothalamic orexins/hypocretins as regulators of breathing. Expert Rev Mol Med 10:e28PubMedCrossRefGoogle Scholar
  104. 104.
    Williams RH, Jensen LT, Verkhratsky A, Fugger L, Burdakov D (2007) Control of hypothalamic orexin neurons by acid and CO2. PNAS 104:10685–10690PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    Yamanaka A, Muraki Y, Tsujino N, Goto K, Sakurai T (2003) Regulation of orexin neurons by the monoaminergic and cholinergic systems. Biochem Biophys Res Commun 303:120–129PubMedCrossRefGoogle Scholar
  106. 106.
    Yamanaka A, Tabuchi S, Tsunematsu T, Fukazawa Y, Tominaga M (2010) Orexin directly excites orexin neurons through orexin 2 receptor. J Neurosci 30:12642–12652PubMedCrossRefGoogle Scholar
  107. 107.
    Yoshioka M, Goda Y, Togashi H, Matsumoto M, Saito H (1992) Pharmacological characterization of 5-hydroxytryptamine-induced apnea in the rat. J Phamacol Exp Ther 260:917–924Google Scholar
  108. 108.
    L-B Yuan, H-L Dong, Zhang H-P, R-N Zhao, Gong G, X-M Chen, L-N Zhang, Xiong L (2011) Neuroprotective effect of orexin-A is mediated by an increase of hypoxia-inducible factor-1 activity in rat. Anesthesiology 114:340–354CrossRefGoogle Scholar
  109. 109.
    Zhu Y, Fenik P, Zhan G, Mazza E, Kelz M, Aston-Jones G, Veasey SC (2007) Selective loss of catecholaminergic wake-active neurons in a murine sleep apnea model. J Neurosci 27:10060–10071PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Nicholas J. Hunt
    • 1
    • 2
  • Karen A. Waters
    • 1
    • 2
    • 3
  • Michael L. Rodriguez
    • 4
    • 5
  • Rita Machaalani
    • 1
    • 2
    • 3
  1. 1.Department of Medicine, Room 206, SIDS and Sleep Apnoea LaboratorySydney Medical School, University of SydneySydneyAustralia
  2. 2.BOSCH Institute of Biomedical ResearchUniversity of SydneySydneyAustralia
  3. 3.The Children’s HospitalWestmeadAustralia
  4. 4.Department of Forensic MedicineNSW Forensic and Analytical Science ServiceSydneyAustralia
  5. 5.Department of PathologySydney Medical School, The University of SydneySydneyAustralia

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