BRAINSTEM MATURATION IN THE SUDDEN INFANT DEATH SYNDROME

Summary

Principal Investigator: Hannah C Kinney
Abstract: The sudden infant death syndrome (SEDS) is the leading cause of postneonatal infant mortality, with an overall incidence of 0.8/1000 live births. Its cause(s) is unknown. Based upon our brainstem studies in SIDS victims during the last grant cycle, we propose an expanded hypothesis concerning the role of the ventral medulla, a region related to chemoreception, autonomic responses, respiratory drive, and thermoregulation, and the neurotransmitter, serotonin (5- HT) in the pathogenesis of SIDS: SIDS, or a subset of SIDS, is due to a developmental abnormality in a ventral medullary network composed of rhombic lip-derived, serotonergic neurons, and this abnormality results in a failure of protective responses to life-threatening challenges (e.g., asphyxia, hypoxia, hypercapnia) during sleep, hi Specific Aims 1-3, we will characterize the normal development of the 5-HT ventral medullary network in brain tissues across early life, the time-period of the pathogenesis of SIDS. We will utilize selected markers to 5-HT cells, terminals, receptor subtypes, and the synthetic enzyme, tryptophan hydroxylase, using tissue autoradiography, immunocytochemistry, and in situ hybridization in brain tissues from human embryos, fetuses, and infants. We will then determine how 5-HT development is abnormal in SIDS victims compared to age-matched controls with the same. 5-HT markers. In Specific Aim 4, we will establish which cell populations derive from the human rhombic lip using cellular and molecular markers to transcription factors implicated in rhombic lip-derivation in animal studies, and we will determine if the affected nuclei in the ventral medullary network in SIDS victims derive from this same embryonic anlage. We will determine if there is an abnormal number of neurons and reactive astrocytes (gliosis) in selected rhombic lip-derived nuclei in SIDS victims. We predict that we will not find gliosis (scarring) in these nuclei, suggesting a developmental, rather than degenerative, defect. Theproposed studies should: substantiate a 5-HT defect in the ventral medulla of SIDS victims;provide insight into the normal development and the molecular and chemical anatomy of the human 5-HT ventral medullary network;and suggest clues about abnormal function in SIDS victims for testing in animal models, and for devising specific preventive strategies and diagnostic tests in human infants.
Funding Period: ----------------1992 - ---------------2010-
more information: NIH RePORT

Top Publications

  1. ncbi Serotonergic and glutamatergic neurons at the ventral medullary surface of the human infant: Observations relevant to central chemosensitivity in early human life
    David S Paterson
    Department of Pathology, Enders 1111, Children s Hospital, 300 Longwood Avenue, Boston, MA 02115, United States Harvard Medical School, Boston, MA 02115, USA
    Auton Neurosci 124:112-24. 2006
  2. ncbi Caffeine improves the ability of serotonin-deficient (Pet-1-/-) mice to survive episodic asphyxia
    Kevin J Cummings
    Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA
    Pediatr Res 73:38-45. 2013
  3. pmc Risk factor changes for sudden infant death syndrome after initiation of Back-to-Sleep campaign
    Felicia L Trachtenberg
    New England Research Institutes, Watertown, Massachusetts, USA
    Pediatrics 129:630-8. 2012
  4. pmc Decreased GABAA receptor binding in the medullary serotonergic system in the sudden infant death syndrome
    Kevin G Broadbelt
    Department of Pathology, Children s Hospital Boston and Harvard Medical School, Boston, MA 02115, USA
    J Neuropathol Exp Neurol 70:799-810. 2011
  5. pmc SweetSEQer, simple de novo filtering and annotation of glycoconjugate mass spectra
    Oliver Serang
    Departments of Neurobiology, Harvard Medical School, Boston, Massachusetts 02119, USA
    Mol Cell Proteomics 12:1735-40. 2013
  6. ncbi Multiple serotonergic brainstem abnormalities in sudden infant death syndrome
    David S Paterson
    Department of Pathology, Children s Hospital Boston and Harvard Medical School, Boston, MA, USA
    JAMA 296:2124-32. 2006
  7. ncbi The development of the medullary serotonergic system in early human life
    Hannah C Kinney
    Department of Pathology, Children s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Auton Neurosci 132:81-102. 2007
  8. pmc The development of nicotinic receptors in the human medulla oblongata: inter-relationship with the serotonergic system
    Jhodie R Duncan
    Department of Pathology, Children s Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA
    Auton Neurosci 144:61-75. 2008
  9. pmc Interleukin-6 and the serotonergic system of the medulla oblongata in the sudden infant death syndrome
    Ingvar Jon Rognum
    Department of Pathology, Children s Hospital Boston, Harvard Medical School, Boston, MA, USA
    Acta Neuropathol 118:519-30. 2009
  10. pmc Brainstem deficiency of the 14-3-3 regulator of serotonin synthesis: a proteomics analysis in the sudden infant death syndrome
    Kevin G Broadbelt
    Department of Pathology, Children s Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA
    Mol Cell Proteomics 11:M111.009530. 2012

Scientific Experts

  • Hannah C Kinney
  • David S Paterson
  • Kevin G Broadbelt
  • Kevin J Cummings
  • Felicia L Trachtenberg
  • Jhodie R Duncan
  • Eugene E Nattie
  • Oliver Serang
  • Aihua Li
  • Kathryn G Commons
  • Elisabeth A Haas
  • Henry F Krous
  • Christina Stanley
  • Ingvar Jon Rognum
  • Jan Muntel
  • Gary McDowell
  • Richard S Lee
  • Hanno Steen
  • John W Froehlich
  • Judith A Steen
  • John A Daubenspeck
  • Julie C Hewitt
  • Richard A Belliveau
  • Natalia S Borenstein
  • Jill M Hoffman
  • David J Mokler
  • Robin L Haynes
  • May Yang
  • Torleiv O Rognum
  • Ashild Vege

Detail Information

Publications16

  1. ncbi Serotonergic and glutamatergic neurons at the ventral medullary surface of the human infant: Observations relevant to central chemosensitivity in early human life
    David S Paterson
    Department of Pathology, Enders 1111, Children s Hospital, 300 Longwood Avenue, Boston, MA 02115, United States Harvard Medical School, Boston, MA 02115, USA
    Auton Neurosci 124:112-24. 2006
    ..These data are important towards delineating the role of the human Arc in modulation of homeostasis, and its dysfunction in brainstem-associated pathologies such as the sudden infant death syndrome...
  2. ncbi Caffeine improves the ability of serotonin-deficient (Pet-1-/-) mice to survive episodic asphyxia
    Kevin J Cummings
    Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA
    Pediatr Res 73:38-45. 2013
    ..We hypothesized that caffeine, a respiratory stimulant, would hasten the onset of gasping and improve autoresuscitation in 5-HT-deficient, Pet-1(-/-) mice...
  3. pmc Risk factor changes for sudden infant death syndrome after initiation of Back-to-Sleep campaign
    Felicia L Trachtenberg
    New England Research Institutes, Watertown, Massachusetts, USA
    Pediatrics 129:630-8. 2012
    ..To test the hypothesis that the profile of sudden infant death syndrome (SIDS) changed after the Back-to-Sleep (BTS) campaign initiation, document prevalence and patterns of multiple risks, and determine the age profile of risk factors...
  4. pmc Decreased GABAA receptor binding in the medullary serotonergic system in the sudden infant death syndrome
    Kevin G Broadbelt
    Department of Pathology, Children s Hospital Boston and Harvard Medical School, Boston, MA 02115, USA
    J Neuropathol Exp Neurol 70:799-810. 2011
    ..026). These data suggest that medullary GABAA receptors are abnormal in SIDS infants and that SIDS is a complex disorder of a homeostatic network in the medulla that involves deficits of the GABAergic and 5-HT systems...
  5. pmc SweetSEQer, simple de novo filtering and annotation of glycoconjugate mass spectra
    Oliver Serang
    Departments of Neurobiology, Harvard Medical School, Boston, Massachusetts 02119, USA
    Mol Cell Proteomics 12:1735-40. 2013
    ..This study presents a novel tool for annotating spectra and producing glycan graphs from LC-MS/MS spectra. The tool is evaluated and shown to perform similarly to an expert on manually curated data...
  6. ncbi Multiple serotonergic brainstem abnormalities in sudden infant death syndrome
    David S Paterson
    Department of Pathology, Children s Hospital Boston and Harvard Medical School, Boston, MA, USA
    JAMA 296:2124-32. 2006
    ..Previously, abnormalities in 5-HT receptor binding in the medullae of infants dying from sudden infant death syndrome (SIDS) were identified, suggesting that medullary 5-HT dysfunction may be responsible for a subset of SIDS cases...
  7. ncbi The development of the medullary serotonergic system in early human life
    Hannah C Kinney
    Department of Pathology, Children s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Auton Neurosci 132:81-102. 2007
    ..Thus, protracted changes occur from the prenatal period through infancy. These data provide a foundation for 5-HT neuronal analysis in pediatric brainstem disorders, as proposed in the sudden infant death syndrome...
  8. pmc The development of nicotinic receptors in the human medulla oblongata: inter-relationship with the serotonergic system
    Jhodie R Duncan
    Department of Pathology, Children s Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA
    Auton Neurosci 144:61-75. 2008
    ..This study indicates parallel dynamic and complex changes in the medullary nicotinic and 5-HT systems throughout early life, i.e., the period of risk for SIDS...
  9. pmc Interleukin-6 and the serotonergic system of the medulla oblongata in the sudden infant death syndrome
    Ingvar Jon Rognum
    Department of Pathology, Children s Hospital Boston, Harvard Medical School, Boston, MA, USA
    Acta Neuropathol 118:519-30. 2009
    ..Aberrant interactions between IL-6 and the arcuate nucleus may contribute to impaired responses to hypercapnia generated by infection (hyper-metabolism) combined with rebreathing...
  10. pmc Brainstem deficiency of the 14-3-3 regulator of serotonin synthesis: a proteomics analysis in the sudden infant death syndrome
    Kevin G Broadbelt
    Department of Pathology, Children s Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA
    Mol Cell Proteomics 11:M111.009530. 2012
    ..These data suggest a potential molecular defect in SIDS related to TPH2 regulation, as 14-3-3 is critical in this process...
  11. pmc Failed heart rate recovery at a critical age in 5-HT-deficient mice exposed to episodic anoxia: implications for SIDS
    Kevin J Cummings
    Department of Physiology and Neurobiology, Dartmouth Medical School, Lebanon, New Hampshire, USA
    J Appl Physiol (1985) 111:825-33. 2011
    ..They may apply to the sudden infant death syndrome, which occurs at a critical age and is associated with 5-HT deficiency...
  12. pmc The serotonergic anatomy of the developing human medulla oblongata: implications for pediatric disorders of homeostasis
    Hannah C Kinney
    Department of Pathology, Children s Hospital Boston and Harvard Medical School, Boston, MA 02115, United States
    J Chem Neuroanat 41:182-99. 2011
    ..The delineation of the development and organization of the human caudal 5-HT system provides the critical foundation for the neuropathologic elucidation of its disorders directly in the human brain...
  13. pmc 5-HT2A receptors are concentrated in regions of the human infant medulla involved in respiratory and autonomic control
    David S Paterson
    Department of Pathology, Children s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
    Auton Neurosci 147:48-55. 2009
    ....
  14. pmc The brainstem and serotonin in the sudden infant death syndrome
    Hannah C Kinney
    Department of Pathology, Children s Hospital Boston and Harvard Medical School, Boston, MA 02115, USA
    Annu Rev Pathol 4:517-50. 2009
    ..These emerging data suggest an important underlying mechanism in SIDS that may help lead to identification of infants at risk and specific interventions to prevent death...
  15. pmc Brainstem serotonergic deficiency in sudden infant death syndrome
    Jhodie R Duncan
    Department of Pathology, Children s Hospital Boston, 300 Longwood Ave, Boston, MA 02115, USA
    JAMA 303:430-7. 2010
    ..Abnormalities of serotonin (5-hydroxytryptamine [5-HT]) receptor binding in regions of the medulla oblongata involved in this control have been reported in infants dying from SIDS...