Skip to main content
SpringerLink
Log in
Book cover

Sudden Infant Death Syndrome pp 15–25Cite as

Developmental Alteration of Hypocretins (Orexins) in the Brainstem in the Sudden Infant Death Syndrome

  • Chapter
  • First Online:

  • 987 Accesses

Abstract

Objective: The hypocretins (orexins) (HCRT), which help regulate aspects of sleep and wakefulness, are synthesized by neurons located exclusively in the lateral hypothalamus. Hcrt-containing neurons project throughout the CNS and project especially heavily to the noradrenergic locus coeruleus (LC). Sudden infant death syndrome (SIDS) remains the principal cause of postneonatal infant death, but mechanisms underlying the syndrome have not been completely elucidated. Recently, failure to arouse from sleep has been suggested as contributing to SIDS. Therefore, we studied developmental changes in HCRT-1 and HCRT-2 in the brainstem and compared those changes between SIDS cases and controls. Methods: Twenty cases of SIDS and 21 controls, aged from 20 gestational weeks to 13 years of age, were selected. We examined the brainstems of each subject for HCRT-1 and HCRT-2 with immunohistochemistry techniques. Results: HCRT-1 appeared in the brainstem from the early fetal period. Its expression was moderately present at 6 months in the LC, dorsal raphe nucleus (DRN), and periaqueductal gray matter (PAG) and then gradually increased during development. HCRT-2 was detected from the neonatal period in the medulla oblongata and LC and from the early fetal period in the DRN and PAG, respectively. Its expression gradually increased from 6 months in the LC, DRN, and PAG. We found intense expression of HCRT-1 in the LC in the SIDS victims earlier than in the controls. No definitive developmental changes emerged in immunoreactivity of HCRT-2 between SIDS cases and controls in the brainstem. Conclusions. This study revealed developmental alterations in HCRT-1, a peptide related to arousal, in the LC of SIDS victims relative to controls, suggesting that the hypothalamic-pontine hypocretinergic system is involved in the pathophysiology of SIDS.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

DRN:

Dorsal raphe nucleus

HCRT:

Hypocretin

LC:

Locus coeruleus

LDT:

Laterodorsal tegmental nucleus

REM:

Rapid eye movements

SIDS:

Sudden infant death syndrome

References

  1. Mitchell EA, Tuohy JM, Brunt JM et al (1997) Risk factors for sudden infant death syndrome following the prevention campaign in New Zealand: a prospective study. Pediatrics 100:835–840

    Article  PubMed  CAS  Google Scholar 

  2. Dwyer T, Ponsonby AL (1996) Sudden infant death syndrome: after the “back to sleep” campaign. BMJ 313:180–181

    Article  PubMed  CAS  Google Scholar 

  3. Willinger M, James LS, Catz C (1991) Defining the sudden infant death syndrome (SIDS): deliberations of an expert panel convened by the National Institute of Child Health and Human Development. Pediatr Pathol 11:677–684

    Article  PubMed  CAS  Google Scholar 

  4. Takashima S, Armstrong D, Becker LE et al (1978) Cerebral white matter lesions in the sudden infant death syndrome. Pediatrics 62:155–159

    PubMed  CAS  Google Scholar 

  5. Becker LE, Takashima S (1985) Chronic hypoventilation and development of brain stem gliosis. Neuropediatrics 16:19–23

    Article  PubMed  CAS  Google Scholar 

  6. Kinney HC, Burger PC, Harrell FE et al (1983) “Reactive gliosis” in the medulla oblongata of victims of the sudden infant death syndrome. Pediatrics 72:181–187

    PubMed  CAS  Google Scholar 

  7. Takashima S, Armstrong D, Becker LE et al (1978) Cerebral hypoperfusion in the sudden infant death syndrome? Brain stem gliosis and vasculature. Ann Neurol 4:257–262

    Article  PubMed  CAS  Google Scholar 

  8. Quattrochi JJ, McBride PT, Yates AJ (1985) Brainstem immaturity in sudden infant death syndrome: a quantitative rapid Golgi study of dendritic spines in 95 infants. Brain Res 325:39–48

    Article  PubMed  CAS  Google Scholar 

  9. Takashima S, Becker LE (1986) Prenatal and postnatal maturation of medullary “respiratory centers”. Dev Brain Res 26:173–177

    Article  Google Scholar 

  10. Takashima S, Becker LE (1985) Developmental abnormalities of medullary respiratory centers in sudden infant death syndrome. Exp Neurol 90:580–587

    Article  PubMed  CAS  Google Scholar 

  11. Kinney HC, Brody BA, Finkelstein SP et al (1992) Delayed central nervous system myelination in the sudden infant death syndrome. J Neuropathol Exp Neurol 51:115–126

    Article  PubMed  CAS  Google Scholar 

  12. Newman NM, Trindler JA, Phillips KA et al (1989) Arousal deficit: mechanisms of the sudden infant death syndrome? Aust Paediatr J 25:196–201

    PubMed  CAS  Google Scholar 

  13. de Lecea L, Kilduff TS, Peyron C et al (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95:322–327

    Article  PubMed  Google Scholar 

  14. Sakurai T, Amemiya A, Ishii M et al (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585

    Article  PubMed  CAS  Google Scholar 

  15. Kilduff TS, Peyron C (2000) The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci 23:359–365

    Article  PubMed  CAS  Google Scholar 

  16. Hagan JJ, Leslie RA, Patel S et al (1999) Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci USA 96:10911–10916

    Article  PubMed  CAS  Google Scholar 

  17. Bourgin P, Huitron-Resendiz S, Spier AD et al (2000) Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci 20:7760–7765

    PubMed  CAS  Google Scholar 

  18. Piper DC, Upton N, Smith MI et al (2000) The novel brain neuropeptide, orexin-A, modulates the sleep-wake cycle of rats. Eur J Neurosci 12:726–730

    Article  PubMed  CAS  Google Scholar 

  19. Xi M, Morales FR, Chase MH (2001) Effects on sleep and wakefulness of the injection of hypocretin-1 (orexin-A) into the laterodorsal tegmental nucleus of the cat. Brain Res 901:259–264

    Article  PubMed  CAS  Google Scholar 

  20. Espana RA, Baldo BA, Kelley AE et al (2001) Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action. Neuroscience 106:699–715

    Article  PubMed  CAS  Google Scholar 

  21. Nishino S, Ripley B, Overeem S et al (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355:39–40

    Article  PubMed  CAS  Google Scholar 

  22. Thannickal TC, Moore RY, Nienhuis R et al (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27:469–474

    Article  PubMed  CAS  Google Scholar 

  23. Peyron C, Tighe DK, van den Pol AN et al (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18:9996–10015

    PubMed  CAS  Google Scholar 

  24. Horvath TL, Peyron C, Diano S et al (1999) Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J Comp Neurol 415:145–149

    Article  PubMed  CAS  Google Scholar 

  25. Gomp HS, Aston-Lones G (2008) Role of orexin input in the diurnal rhythm of locus coeruleus impulse activity. Brain Res 1224:43–52

    Article  Google Scholar 

  26. Brown RE, Sergeeve O, Eriksson KS et al (2001) Orexin A excites serotonergic neurons in the dorsal raphe nucleus of the rat. Neuropharmacology 40:457–459

    Article  PubMed  CAS  Google Scholar 

  27. Xi MC, Fung SJ, Yamuy J et al (2002) Induction of active (REM) sleep by microinjection of hypocretin into the nucleus pontis oralis of the cat. J Neurophysiol 87:2880–2888

    PubMed  CAS  Google Scholar 

  28. Dearmoid SJ, Fusco MM, Dewey MM (1989) Coronal sections of the gross brain and brainstem. In: Structure of the human brain: a photographic atlas, vol 3, 3rd edn. Oxford University Press, New York, pp 36–61

    Google Scholar 

  29. Niewenhuys R, Voogd J, van Huijzan J (1988) Transverse sections thorough the brainstem and spinal cord. In: The human central nervous system: a synopsis and atlas, part IV: microsscopial sections, 3rd edn. Springer, Berlin, pp 104–141

    Chapter  Google Scholar 

  30. Shirasaka T, Nakazato M, Matsukura S et al (1999) Sympathetic and cardiovascular actions of orexins in conscious rats. Am J Physiol 277:R1780–R1785

    PubMed  CAS  Google Scholar 

  31. Sweet DC, Levine AS, Billington CJ et al (1999) Feeding response to central orexins. Brain Res 821:535–538

    Article  PubMed  CAS  Google Scholar 

  32. Nambu T, Sakurai T, Mizukami K et al (1999) Distribution of orexin neurons in the adult rat brain. Brain Res 827:243–260

    Article  PubMed  CAS  Google Scholar 

  33. Zhang J-H, Sampogna S, Morales FR et al (2004) Distribution of hypocretin (orexin) immunoreactivity in the feline pons and medulla. Brain Res 995:205–217

    Article  PubMed  CAS  Google Scholar 

  34. Yamamoto Y, Ueta Y, Hara Y et al (2000) Postnatal development of orexin/hypocretin in rats. Mol Brain Res 78:108–119

    Article  PubMed  CAS  Google Scholar 

  35. Stoyanova II, Rutten WL, le Feber J (2010) Orexin-A and orexin-B during the postnatal development of the rat brain. Cell Mol Neurobiol 30:81–89

    Article  PubMed  CAS  Google Scholar 

  36. van den Pol AN, Patrylo PR, Ghosh PK et al (2001) Lateral hypothalamus: early developmental expression and response to hypocretin (orexin). J Comp Neurol 433:349–363

    Article  Google Scholar 

  37. Steininger TL, Kilduff TS, Behan M et al (2004) Comparison of hypocretin/orexin and melanin-concentrating hormone neurons and axonal projections in the embryonic and postnatal rat brain. J Chem Neuroanat 27:165–181

    Article  PubMed  CAS  Google Scholar 

  38. Kobayashi T, Yano T, Ishiguro H et al (2002) Hypocretin-1 (orexin-A) levels in human lumbar CSF in different age groups: infants to elderly persons. Sleep 25:337–339

    Google Scholar 

  39. Frank MG, Heller HC (1997) Development of diurnal organization of EEG slow-wave activity and slow-wave sleep in the rat. Am J Physiol 273:R472–R478

    PubMed  CAS  Google Scholar 

  40. Frank MG, Heller HC (1997) Development of REM and slow wave sleep in the rat. Am J Physiol 272:1792–1799

    Google Scholar 

  41. Bernard R, Lydic R, Baghdoyan HA (2003) Hypocretin-1 causes G protein activation and increases Ach release in rat pons. Eur J Neurosci 18:1775–1785

    Article  PubMed  Google Scholar 

  42. Date Y, Ueta Y, Yamashita H et al (1999) Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulator systems. Proc Natl Acad Sci USA 96:748–753

    Article  PubMed  CAS  Google Scholar 

  43. Lidov HG, Molliver ME (1982) An immunohistochemical study of serotonin neuron development in the rat: ascending pathways and terminal fields. Brain Res Bull 8:389–430

    Article  PubMed  CAS  Google Scholar 

  44. Lidov HG, Molliver ME (1982) Immunohistochemical study of the development of serotonergic neurons in the rat CNS. Brain Res Bull 9:559–604

    Article  PubMed  CAS  Google Scholar 

  45. Levitt P, Moore RY (1979) Development of the noradrenergic innervation of the neocortex. Brain Res 162:243–259

    Article  PubMed  CAS  Google Scholar 

  46. Yamanaka A, Muraki Y, Ichiki K et al (2006) Orexin neurons are directly and indirectly regulated by catecholamines in a complex manner. J Neurophysiol 96:284–298

    Article  PubMed  CAS  Google Scholar 

  47. van den Pol AN, Ghosh PK, Liu R-J et al (2002) Hypocretin (orexin) enhances neuron activity and cell synchrony in developing mouse GFP-expressing locus coeruleus. J Physiol 541:169–185

    Article  PubMed  Google Scholar 

Download references

Acknowledgement

This study was supported by grants from the Ministry of Health, Labor and Welfare of Japan.

Author information

Authors and Affiliations

  1. Department of Neonatology, School of Medicine, Toho University, 6-11-1 Ohmorinishi, Ohta, Tokyo, 143-8541, Japan

    Yuri Ozawa & Naoki Uga

  2. Shimada Ryoiku Center Hachiouji (Institution for Persons with Severe Motor and Intellectual Disabilities), Tokyo, Japan

    Yuri Ozawa

  3. Yanagawa Institution for Development Disabilities, Internal University of Health and Welfare, Yanagawa, Fukuoka, Japan

    Sachio Takashima

  4. Department of Surgical Pathology, Ohmori Hospital, School of Medicine, Toho University, Tokyo, Japan

    Hiroko Nonaka

Authors
  1. Yuri Ozawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sachio Takashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroko Nonaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Naoki Uga
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuri Ozawa .

Editor information

Editors and Affiliations

  1. Inst of Advanced Biomedical Engineering Tokyo Women's Medical University, Tokyo, Tokyo, Japan

    Toshiko Sawaguchi

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Japan

About this chapter

Cite this chapter

Ozawa, Y., Takashima, S., Nonaka, H., Uga, N. (2014). Developmental Alteration of Hypocretins (Orexins) in the Brainstem in the Sudden Infant Death Syndrome. In: Sawaguchi, T. (eds) Sudden Infant Death Syndrome. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54315-2_2

Download citation

  • DOI: https://doi.org/10.1007/978-4-431-54315-2_2

  • Published:

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-54314-5

  • Online ISBN: 978-4-431-54315-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation