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

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.

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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

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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.

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The authors report no conflicts of interest.

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Correspondence to Rita Machaalani.

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Hunt, N.J., Waters, K.A., Rodriguez, M.L. et al. Decreased orexin (hypocretin) immunoreactivity in the hypothalamus and pontine nuclei in sudden infant death syndrome. Acta Neuropathol 130, 185–198 (2015). https://doi.org/10.1007/s00401-015-1437-9

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Keywords

  • Human
  • SIDS
  • Development
  • Sleep
  • Sleep dysfunction
  • REM
  • Automated fibre quantification