Abstract
The study aims were twofold: 1) identify the localization and the cytoarchitecture
of the retrotrapezoid nucleus (RTN) in the human fetus and infant and 2) ascertain
if the RTN, given its essential role in animal studies for the maintenance of breathing
and chemoreception, showed abnormalities in victims of sudden perinatal and infant
death (sudden intrauterine unexplained death/SIUD — and sudden infant death syndrome/SIDS).
We examined SIDS and SIUD cases and Controls (n=58) from 34 gestational weeks to 8 months of postnatal age by complete autopsy, in-depth autonomic nervous system histological
examination, and immunohistochemical analysis of the PHOX2B gene, a transcriptional factor involved in Congenital Central Hypoventilation Syndrome
that has been defined as a marker of rat RTN neurons.
We identified a group of PHOX2B-immunopositive neurons within the caudal pons, contiguous
to the facial/parafacial complex, in 90% of Controls, likely the homologous human
RTN (hRTN). We observed structural and/or PHOX2B-expression abnormalities of the hRTN in 71% of SIUD/SIDS cases vs 10% of Controls (p<0.05).
In conclusion we suggest that developmental abnormalities of the hRTN may seriously
compromise chemoreception control, playing a critical role in the pathogenesis of
both SIUD and SIDS.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Autonomic Neuroscience: Basic and ClinicalAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Photostimulation of retrotrapezoid nucleus phox2b-expressing neurons in vivo produces long-lasting activation of breathing in rats.J. Neurosci. 2009; 29: 5806-5819
- Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in Congenital Central Hypoventilation Syndrome.Nat. Genet. 2003; 33: 459-461
- A human mutation in Phox2b causes lack of CO2 chemosensitivity, fatal central apnea and specific loss of parafacial neurons.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 1067-1107
- Breathing with phox2b.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2009; 364: 2477-2483
- Breathing: rhythmicity, plasticity, chemosensitivity.Annu. Rev. Neurosci. 2003; 26: 239-266
- PHOX2B mutations and ventilatory control.Respir. Physiol. Neurobiol. 2008; 164: 49-54
- The brain in chronic CRPS pain: abnormal gray-white matter interactions in emotional and autonomic regions.Neuron. 2008; 60: 570-581
- Regulation of ventral surface chemoreceptors by the central respiratory pattern generator.J. Neurosci. 2005; 25: 8938-8947
- Hypercapnic exposure in Congenital Central Hypoventilation Syndrome reveals CNS respiratory control mechanisms.J. Neurophysiol. 2005; 93: 1647-1658
- The cardiorespiratory control hypothesis for sudden infant death syndrome.Clin. Perinatol. 1992; 19: 757-771
- Central nervous system distribution of the transcription factor Phox2b in the adult rat.J. Comp. Neurol. 2007; 503: 627-641
- Diffusion tensor imaging demonstrates brainstem and cerebellar abnormalities in Congenital Central Hypoventilation Syndrome.Pediatr. Res. 2008; 64: 275-280
- Preliminary study on the cytoarchitecture of the human parabrachial/Kölliker-Fuse complex with reference to sudden infant death syndrome and sudden intrauterine unexplained death.Pediatr. Dev. Pathol. 2004; 7: 171-179
- Hypoplasia of the parafacial/facial complex: a very frequent finding in sudden unexplained fetal death.Open Neurosci. J. 2008; 2: 1-5
- Analysis of the human locus coeruleus in perinatal and infant sudden unexplained death. Possible role of the cigarette smoking in the development of this nucleus.Brain Res. Dev. Brain Res. 2005; 154: 71-80
- Sudden infant death syndrome and sudden intrauterine unexplained death: correlation between hypoplasia of raphé nuclei and serotonin transporter gene promoter polymorphism.Pediatr. Res. 2009; 66: 22-27
- Central chemosensitivity and the reaction theory.J. Physiol. 1982; 332: 1-24
- Techniques and criteria in pathologic and forensic-medical diagnostics of sudden unexpected infant and perinatal death.Am. J. Clin. Pathol. 2005; 124: 259-268
- Guidelines for neuropathologic diagnostics of perinatal unexpected loss and sudden infant death syndrome (SIDS). A technical protocol.Virchows Arch. 2008; 452: 19-25
- Central Chemoreception.in: Dempsey J.A. Pack A.I. Regulation of Breathing. Dekker, M., New York1995: 473-510
- Central chemoreceptors, pH and respiratory control.in: Kaila K. Ransom B.R. pH and Brain Function. Wiley-Liss, New York1998: 536-560
- Retrotrapezoid nucleus lesions decrease phrenic activity and CO2 sensitivity in rats.Respir. Physiol. 1994; 97: 63-77
- Central chemoreception 2005: a brief review.Auton. Neurosci. 2006; 126–127: 332-338
- Lesion in retrotrapezoid nucleus decrease ventilatory output in anesthetized or decerebrate cats.J. Appl. Physiol. 1991; 71: 1364-1375
- Comparative anatomical assessment of the piglet as a model for the developing human medullary serotonergic system.Brain Res. Rev. 2005; 50: 169-183
- A novel functional neuron group for respiratory rhythm generation in the ventral medulla.J. Neurosci. 2003; 23: 1478-1486
- Chemoreceptors and their reflexes with special reference to the fetus and newborn.J. Dev. Physiol. 1981; 3 (Review): 21-57
- Respiratory sensitivity before and after birth.Acta Paediatr. Scand. 1982; 71 (Review): 529-536
- Afferent and efferent connections of the rat retrotrapezoid nucleus.J. Comp. Neurol. 2006; 499: 64-89
- PHOX2B immunolocalization of the candidate human Retrotrapezoid Nucleus.Pediatr. Dev. Pathol. 2010; 13: 291-299
- Magic peptides, magic antibodies: guidelines for appropriate controls for immunohistochemistry.J. Comp. Neurol. 2003; 465: 161-163
- Brainstem projections to the major respiratory neuron populations in the medulla of the cat.J. Comp. Neurol. 1989; 281: 69-96
- Expression of Phox2b by brainstem neurons involved in chemosensory integration in the adult rat.J. Neurosci. 2006; 26: 10305-10314
- Peripheral chemoreceptor inputs to retrotrapezoid nucleus (RTN) CO2-sensitive neurons in rats.J. Physiol. 2006; 572: 503-523
- Selective lesion of retrotrapezoid Phox2b-expressing neurons raises the apnoeic threshold in rats.J. Physiol. 2008; 586: 2975-2991
- Fetal chemoreception: a developing story.Reprod. Fertil. Dev. 1996; 8: 471-482
- The role of respiratory control disorders in SIDS.Respir. Physiol. Neurobiol. 2005; 149: 343-353
- Hypoxic inhibition of breathing and motor activity in the foetus and newborn.Clin. Exp. Pharmacol. Physiol. 1995; 22: 533-536
- Idiopathic Congenital Central Hypoventilation Syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2B.Am. J. Med. Genet. 2003; 123A: 267-278
- Congenital Central Hypoventilation Syndrome (CCHS) and sudden infant death syndrome (SIDS): kindred disorders of autonomic regulation.Respir. Physiol. Neurobiol. 2008; 164 (Review): 38-48
- Congenital Central Hypoventilation Syndrome from past to future: model for translational and transitional autonomic medicine.Pediatr. Pulmonol. 2009; 44 (Review): 521-535
- American Thoracic Society Statement. Congenital Central Hypoventilation Syndrome: Genetic basis, diagnosis, and management.Am. J. Respir. Crit. Care Med. 2010; 181: 626-644
- Central nervous system regulation of reflex responses to hypotension during fetal life.Am. J. Physiol. 1999; 277 (Review): 1541-1552
- Anatomic relationship of the human nucleus of the solitary tract in the medulla oblongata: a DiI labeling study.Auton. Neurosci. 2003; 105: 131-144
Article info
Publication history
Published online: July 16, 2012
Accepted:
June 20,
2012
Received in revised form:
June 16,
2012
Received:
February 16,
2012
Identification
Copyright
© 2012 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
