Decreased Serotonergic Receptor Binding in Rhombic Lip‐Derived Regions of the Medulla Oblongata in the Sudden Infant Death Syndrome

The sudden infant death syndrome (SIDS) is postulated to result from a failure of homeostatic responses to life-threatening challenges (e.g. asphyxia, hypercapnia) during sleep. The ventral medulla participates in sleep-related homeostatic responses, including chemoreception, arousal, airway reflex control, thermoregulation, respiratory drive, and blood pressure regulation, in part via serotonin and its receptors. The ventral medulla in humans contains the arcuate nucleus, in which we have shown isolated defects in muscarinic and kainate receptor binding in SIDS victims. We also have demonstrated that the arcuate nucleus is anatomically linked to the nucleus raphé obscurus, a medullary region with serotonergic neurons. We tested the hypothesis that serotonergic receptor binding is decreased in both the arcuate nucleus and nucleus raphé obscurus in SIDS victims. Using quantitative autoradiography, 3H-lysergic acid diethylamide (3H-LSD binding) to serotonergic receptors (5-HT1A-D and 5-HT2 subtypes) was measured blinded in 19 brainstem nuclei. Cases were classified as SIDS (n = 52), acute controls (infants who died suddenly and in whom a complete autopsy established a cause of death) (n = 15), or chronic cases with oxygenation disorders (n = 17). Serotonergic binding was significantly lowered in the SIDS victims compared with controls in the arcuate nucleus (SIDS, 6 ± 1 fmol/mg tissue; acutes, 19 ± 1; and chronics, 16 ± 1; p = 0.0001) and n. raphé obscurus (SIDS, 28 ± 3 fmol/mg tissue; acutes, 66 ± 6; and chronics, 59 ± 1; p = 0.0001). Binding, however, was also significantly lower (p < 0.05) in 4 other regions that are integral parts of the medullary raphé/serotonergic system, and/or are derived, like the arcuate nucleus and nucleus raphé obscurus, from the same embryonic anlage (rhombic lip). These data suggest that a larger neuronal network than the arcuate nucleus alone is involved in the pathogenesis of SIDS, that is, a network composed of inter-related serotonergic nuclei of the ventral medulla that are involved in homeostatic mechanisms, and/or are derived from a common embryonic anlage.

[1]  J. Coote.  Bulbospinal Serotonergic Pathways in the Control of Blood Pressure , 1990, Journal of cardiovascular pharmacology.

[2]  H. Kinney,et al.  Tritiated-naloxone binding to brainstem opioid receptors in the sudden infant death syndrome. , 1998, Journal of the autonomic nervous system.

[3]  H. Kinney,et al.  Decreased Kainate Receptor Binding in the Arcuate Nucleus of the Sudden Infant Death Syndrome , 1997, Journal of neuropathology and experimental neurology.

[4]  B. Jacobs,et al.  Structure and function of the brain serotonin system. , 1992, Physiological reviews.

[5]  D. Speck,et al.  Origin of serotonin-containing projections to the ventral respiratory group in the rat , 1990, Neuroscience.

[6]  M. Molliver,et al.  Immunohistochemical study of the development of serotonergic neurons in the rat CNS , 1982, Brain Research Bulletin.

[7]  H. Kinney,et al.  Decreased muscarinic receptor binding in the arcuate nucleus in sudden infant death syndrome , 1995, Science.

[8]  I. Törk.  30 – Raphe Nuclei and the Serotonergic System , 1990 .

[9]  L. S. James,et al.  Defining the sudden infant death syndrome (SIDS): deliberations of an expert panel convened by the National Institute of Child Health and Human Development. , 1991, Pediatric pathology.

[10]  H. Kinney,et al.  Sleep influences on homeostatic functions: implications for sudden infant death syndrome. , 2000, Respiration physiology.

[11]  W. T. Peyton,et al.  Origin of the ventral external arcuate fibers and their continuity with the striae medullares of the fourth ventricle of man , 1946, The Journal of comparative neurology.

[12]  R. Bandler,et al.  Finding the failure mechanism in Sudden Infant Death Syndrome , 1998, Nature Medicine.

[13]  G. Richerson.  Sudden Infant Death Syndrome: The Role of Central Chemosensitivity , 1997 .

[14]  R. Mccall,et al.  Identification of serotonergic and sympathetic neurons in medullary raphe nuclei , 1989, Brain Research.

[15]  K. King,et al.  Effect of activation of 5-HT1A receptors at the ventral medulla on phrenic nerve activity. , 1994, European journal of pharmacology.

[16]  G. Richerson,et al.  Chemosensitivity of rat medullary raphe neurones in primary tissue culture , 1998, The Journal of physiology.

[17]  H. Zhuo,et al.  Immunocytochemical studies of the 5‐HT1A receptor in ventral medullary neurons that project to the intermediolateral cell column and contain serotonin or tyrosine hydroxylase immunoreactivity , 1997, The Journal of comparative neurology.

[18]  N. Cherniack,et al.  CO2-induced c-fos expression in the CNS catecholaminergic neurons. , 1996, Respiration physiology.

[19]  Wilhelm Harkmark,et al.  Cell migrations from the rhombic lip to the inferior olive, the nucleus raphe and the pons. A morphological and experimental investigation on chick embryos , 1954, The Journal of comparative neurology.

[20]  N. Nisimaru,et al.  Cerebellar control of the cardiovascular responses during postural changes in conscious rabbits , 1998, Neuroscience Research.

[21]  G. Bishop,et al.  Topographical organization in the origin of serotoninergic projections to different regions of the cat cerebellar cortex , 1991, The Journal of comparative neurology.

[22]  C. Essick.  The development of the nuclei pontis and the nucleus arcuatus in man , 1912 .

[23]  R. Stremel,et al.  Involvement of the raphe in the respiratory effects of gigantocellular area activation , 1990, Brain Research Bulletin.

[24]  A. Loewy,et al.  CNS cell groups projecting to sympathetic outflow of tail artery: neural circuits involved in heat loss in the rat , 1998, Brain Research.

[25]  Ronald M. Harper,et al.  Dorsal raphe neurons: depression of firing during sleep in cats , 1976, Brain Research.

[26]  R. Mccall.  Evidence for a serotonergically mediated sympathoexcitatory response to stimulation of medullary raphe nuclei , 1984, Brain Research.

[27]  T. Dick,et al.  Involvement of serotonin in the excitation of phrenic motoneurons evoked by stimulation of the raphe obscurus , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[28]  R. Bandler,et al.  Hypotension following acute hypovolaemia depends on the caudal midline medulla , 1998, Neuroreport.

[29]  S. Morrison.  RVLM and raphe differentially regulate sympathetic outflows to splanchnic and brown adipose tissue. , 1999, American journal of physiology. Regulatory, integrative and comparative physiology.

[30]  H. Kinney,et al.  A perspective on neuropathologic findings in victims of the sudden infant death syndrome: the triple-risk model. , 1994, Biology of the neonate.

[31]  E. Nattie,et al.  Evidence for central chemoreception in the midline raphé. , 1996, Journal of applied physiology.

[32]  Hitoshi Takahashi,et al.  Distribution of serotonin-containing cell bodies in the brainstem of the human fetus determined with immunohistochemistry using antiserotonin serum , 1986, Brain and Development.

[33]  H. Kinney,et al.  Anatomic Relationships of the Human Arcuate Nucleus of the Medulla: A Dil‐Labeling Study , 1997, Journal of neuropathology and experimental neurology.

[34]  J C Smith,et al.  Brainstem projections to the major respiratory neuron populations in the medulla of the cat , 1989, The Journal of comparative neurology.

[35]  S. Rees,et al.  Reduction in choline acetyltransferase immunoreactivity but not muscarinic-m2 receptor immunoreactivity in the brainstem of SIDS infants. , 1999, Journal of neuropathology and experimental neurology.

[36]  A. Loewy.  Raphe pallidus and raphe obscurus projections to the intermediolateral cell column in the rat , 1981, Brain Research.

[37]  J Lee,et al.  REGIONAL BRAIN ACTIVATION IN HUMANS DURING RESPIRATORY AND BLOOD PRESSURE CHALLENGES , 1998, Clinical and experimental pharmacology & physiology.

[38]  H. Kinney,et al.  Arcuate Nucleus Hypoplasia in the Sudden Infant Death Syndrome , 1992, Journal of neuropathology and experimental neurology.

[39]  H. Baumgarten,et al.  Serotoninergic Neurons and 5-HT Receptors in the CNS , 2000, Handbook of Experimental Pharmacology.

[40]  A. Bjo¨rklund,et al.  The indolaminergic innervation of the inferior olive. 1. Convergence with the direct spinal afferents in the areas projecting to the cerebellar anterior lobe , 1977, Brain Research.

[41]  S. Manaker.,et al.  Origin of serotoninergic afferents to the hypoglossal nucleus in the rat , 1993, The Journal of comparative neurology.

[42]  G. L. Gebber,et al.  Subgroups of rostral ventrolateral medullary and caudal medullary raphe neurons based on patterns of relationship to sympathetic nerve discharge and axonal projections. , 1997, Journal of neurophysiology.

[43]  O. S. Strong.  A case of unilateral cerebellar agenesia , 1915 .

[44]  G. Bishop,et al.  The origin of serotoninergic afferents to the cat's cerebellar nuclei , 1994, The Journal of comparative neurology.

[45]  R. Llinás,et al.  Serotonin Modulation of Inferior Olivary Oscillations and Synchronicity: A Multiple‐electrode Study in the Rat Cerebellum , 1995, The European journal of neuroscience.

[46]  S. Matsuo,et al.  Projection of respiratory neurons in rat medullary raphé nuclei to the phrenic nucleus. , 1998, Respiration physiology.

[47]  R. Martin,et al.  Role of the medullary raphe nuclei in the respiratory response to CO2. , 1998, Respiration physiology.

[48]  H. Folgering,et al.  Primary alveolar hypoventilation (Ondine's curse syndrome) in an infant without external arcuate nucleus. Case report. , 1979, Bulletin europeen de physiopathologie respiratoire.

[49]  M. Willinger.  Defining the sudden infant death syndrome (SIDS) , 1991 .

[50]  H. Kinney,et al.  Developmental Changes in [3H]Lysergic Acid Diethylamide ([3H]LSD) Binding to Serotonin Receptors in the Human Brainstem , 1996, Journal of neuropathology and experimental neurology.

[51]  B. Jacobs,et al.  Response of serotonergic caudal raphe neurons in relation to specific motor activities in freely moving cats , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[52]  S. Salamat,et al.  Atlas of the Human Brainstem , 1997 .

[53]  D. Morin,et al.  Changes in serotonin metabolism may elicit obstructive apnoea in the newborn rat. , 1993, The Journal of physiology.

[54]  Chris I. De Zeeuw,et al.  GATA-3 Is Involved in the Development of Serotonergic Neurons in the Caudal Raphe Nuclei , 1999, The Journal of Neuroscience.

[55]  J. Fleiss.  The design and analysis of clinical experiments , 1987 .

[56]  G. Allen,et al.  Serotoninergic and nonserotoninergic neurons in the medullary raphe system have axon collateral projections to autonomic and somatic cell groups in the medulla and spinal cord , 1994, The Journal of comparative neurology.

[57]  H. Kinney,et al.  Candidate cell populations for respiratory chemosensitive fields in the human infant medulla , 1990, The Journal of comparative neurology.

[58]  H. Kinney,et al.  Brainstem 3H-Nicotine Receptor Binding in the Sudden Infant Death Syndrome , 1998, Journal of neuropathology and experimental neurology.

[59]  H. Baumgarten,et al.  Anatomy of central serotoninergic projection systems , 2000 .

[60]  E. T. Pierce.  Histogenesis of the nuclei griseum pontis, corporis pontobulbaris and reticularis tegmenti pontis (Bechterew) in the mouse an autoradiographic study , 1966 .