{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T21:48:16Z","timestamp":1774993696769,"version":"3.50.1"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T00:00:00Z","timestamp":1640044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001524","name":"CJ Foundation for SIDS","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001524","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010320","name":"Cooper Trewin Memorial SUDC Research Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010320","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013304","name":"CJ First Candle","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013304","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:p>Sudden infant death syndrome (SIDS) is understood as a syndrome that presents with the common phenotype of sudden death but involves heterogenous biological causes. Many pathological findings have been consistently reported in SIDS, notably in areas of the brain known to play a role in autonomic control and arousal. Our laboratory has reported abnormalities in SIDS cases in medullary serotonin (5-HT) receptor<jats:sub>1A<\/jats:sub>and within the dentate gyrus of the hippocampus. Unknown, however, is whether the medullary and hippocampal abnormalities coexist in the same SIDS cases, supporting a biological relationship of one abnormality with the other. In this study, we begin with an analysis of medullary 5-HT<jats:sub>1A<\/jats:sub>binding, as determined by receptor ligand autoradiography, in a combined cohort of published and unpublished SIDS (<jats:italic>n<\/jats:italic>= 86) and control (<jats:italic>n<\/jats:italic>= 22) cases. We report 5-HT<jats:sub>1A<\/jats:sub>binding abnormalities consistent with previously reported data, including lower age-adjusted mean binding in SIDS and age vs. diagnosis interactions. Utilizing this combined cohort of cases, we identified 41 SIDS cases with overlapping medullary 5-HT<jats:sub>1A<\/jats:sub>binding data and hippocampal assessment and statistically addressed the relationship between abnormalities at each site. Within this SIDS analytic cohort, we defined abnormal (low) medullary 5-HT<jats:sub>1A<\/jats:sub>binding as within the lowest quartile of binding adjusted for age and we examined three specific hippocampal findings previously identified as significantly more prevalent in SIDS compared to controls (granular cell bilamination, clusters of immature cells in the subgranular layer, and single ectopic cells in the molecular layer of the dentate gyrus). Our data did not find a strong statistical relationship between low medullary 5-HT<jats:sub>1A<\/jats:sub>binding and the presence of any of the hippocampal abnormalities examined. It did, however, identify a subset of SIDS (~25%) with both low medullary 5-HT<jats:sub>1A<\/jats:sub>binding and hippocampal abnormalities. The subset of SIDS cases with both low medullary 5-HT<jats:sub>1A<\/jats:sub>binding and single ectopic cells in the molecular layer was associated with prenatal smoking (<jats:italic>p<\/jats:italic>= 0.02), suggesting a role for the exposure in development of the two abnormalities. Overall, our data present novel information on the relationship between neuropathogical abnormalities in SIDS and support the heterogenous nature and overall complexity of SIDS pathogenesis.<\/jats:p>","DOI":"10.3389\/fped.2021.762017","type":"journal-article","created":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T05:25:32Z","timestamp":1640064332000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Medullary Serotonergic Binding Deficits and Hippocampal Abnormalities in Sudden Infant Death Syndrome: One or Two Entities?"],"prefix":"10.3389","volume":"9","author":[{"given":"Robin L.","family":"Haynes","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah C.","family":"Kinney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth A.","family":"Haas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jhodie R.","family":"Duncan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Molly","family":"Riehs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felicia","family":"Trachtenberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dawna D.","family":"Armstrong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanda","family":"Alexandrescu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane B.","family":"Cryan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco M.","family":"Hefti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry F.","family":"Krous","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard D.","family":"Goldstein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynn A.","family":"Sleeper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1093\/jnen\/59.5.377","article-title":"Decreased serotonergic receptor binding in rhombic lip-derived regions of the medulla oblongata in the sudden infant death syndrome","volume":"59","author":"Panigrahy","year":"2000","journal-title":"J Neuropathol Exp Neurol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1093\/jnen\/60.3.228","article-title":"Medullary serotonergic network deficiency in the sudden infant death syndrome: review of a 15-year study of a single dataset","volume":"60","author":"Kinney","year":"2001","journal-title":"J Neuropathol Exp Neurol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1178","DOI":"10.1093\/jnen\/62.11.1178","article-title":"Serotonergic brainstem abnormalities in Northern Plains Indians with the sudden infant death syndrome","volume":"62","author":"Kinney","year":"2003","journal-title":"J Neuropathol Exp Neurol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2124","DOI":"10.1001\/jama.296.17.2124","article-title":"Multiple serotonergic brainstem abnormalities in sudden infant death syndrome","volume":"296","author":"Paterson","year":"2006","journal-title":"JAMA."},{"key":"B5","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1001\/jama.2010.45","article-title":"Brainstem serotonergic deficiency in sudden infant death syndrome","volume":"303","author":"Duncan","year":"2010","journal-title":"JAMA."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1016\/S0028-3908(99)00010-6","article-title":"A review of central 5-HT receptors and their function","volume":"38","author":"Barnes","year":"1999","journal-title":"Neuropharmacology."},{"key":"B7","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1007\/s00401-008-0468-x","article-title":"Serotoninergic receptor 1A in the sudden infant death syndrome brainstem medulla and associations with clinical risk factors","volume":"117","author":"Machaalani","year":"2009","journal-title":"Acta Neuropathol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1007\/s00401-014-1357-0","article-title":"Dentate gyrus abnormalities in sudden unexplained death in infants: morphological marker of underlying brain vulnerability","volume":"129","author":"Kinney","year":"2015","journal-title":"Acta Neuropathol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"208","DOI":"10.2350\/06-08-0144.1","article-title":"Sudden death in toddlers associated with developmental abnormalities of the hippocampus: a report of five cases","volume":"10","author":"Kinney","year":"2007","journal-title":"Pediatr Dev Pathol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"455","DOI":"10.2350\/08-09-0542.1","article-title":"Sudden death, febrile seizures, and hippocampal and temporal lobe maldevelopment in toddlers: a new entity","volume":"12","author":"Kinney","year":"2009","journal-title":"Pediatr Dev Pathol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1007\/s12024-012-9367-5","article-title":"Hippocampal asymmetry and sudden unexpected death in infancy: a case report","volume":"8","author":"Rodriguez","year":"2012","journal-title":"Forensic Sci Med Pathol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1007\/s12024-015-9731-3","article-title":"Hippocampal malformation associated with sudden death in early childhood: a neuropathologic study: part 2 of the investigations of The San Diego SUDC Research Project","volume":"12","author":"Hefti","year":"2016","journal-title":"Forensic Sci Med Pathol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1007\/s12024-015-9724-2","article-title":"Sudden unexpected death in early childhood: general observations in a series of 151 cases: part 1 of the investigations of the San Diego SUDC Research Project","volume":"12","author":"Hefti","year":"2016","journal-title":"Forensic Sci Med Pathol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1093\/jnen\/nlw075","article-title":"Hippocampal formation maldevelopment and sudden unexpected death across the pediatric age spectrum","volume":"75","author":"Kinney","year":"2016","journal-title":"J Neuropathol Exp Neurol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1007\/s12024-020-00268-7","article-title":"Hippocampal abnormalities and seizures: a 16-year single center review of sudden unexpected death in childhood, sudden unexpected death in epilepsy and SIDS","volume":"16","author":"Kon","year":"2020","journal-title":"Forensic Sci Med Pathol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/0006-8993(90)91601-C","article-title":"Granule cell dispersion in the dentate gyrus of humans with temporal lobe epilepsy","volume":"535","author":"Houser","year":"1990","journal-title":"Brain Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1097\/00005072-199309000-00001","article-title":"The neuropathology of temporal lobe epilepsy","volume":"52","author":"Armstrong","year":"1993","journal-title":"J Neuropathol Exp Neurol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1007\/s10024-005-0054-3","article-title":"Epilepsy-induced microarchitectural changes in the brain","volume":"8","author":"Armstrong","year":"2005","journal-title":"Pediatr Dev Pathol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1007\/s00401-009-0512-5","article-title":"Towards a clinico-pathological classification of granule cell dispersion in human mesial temporal lobe epilepsies","volume":"117","author":"Blumcke","year":"2009","journal-title":"Acta Neuropathol."},{"key":"B20","first-page":"55","article-title":"State-related physiological changes and risk for the sudden infant death syndrome","volume":"22","author":"Harper","year":"1986","journal-title":"Aust Paediatr J."},{"key":"B21","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1111\/j.1528-1167.2010.02908.x","article-title":"The serotonin axis: shared mechanisms in seizures, depression, and SUDEP","volume":"52","author":"Richerson","year":"2011","journal-title":"Epilepsia."},{"key":"B22","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1007\/978-3-0348-7259-1_5","article-title":"Role of serotonin and other neurotransmitter receptors in brain development: basis for developmental pharmacology","volume":"43","author":"Whitaker-Azmitia","year":"1991","journal-title":"Pharmacol Rev."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1038\/nrn1256","article-title":"The developmental role of serotonin: news from mouse molecular genetics","volume":"4","author":"Gaspar","year":"2003","journal-title":"Nat Rev Neurosci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1652","DOI":"10.1523\/JNEUROSCI.4651-03.2004","article-title":"Early serotonergic projections to Cajal-Retzius cells: relevance for cortical development","volume":"24","author":"Janusonis","year":"2004","journal-title":"J Neurosci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1016\/j.tins.2010.05.005","article-title":"Serotonin: a regulator of neuronal morphology and circuitry","volume":"33","author":"Daubert","year":"2010","journal-title":"Trends Neurosci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2711","DOI":"10.1523\/JNEUROSCI.4331-15.2016","article-title":"Impaired Serotonergic Brainstem Function during and after Seizures","volume":"36","author":"Zhan","year":"2016","journal-title":"J Neurosci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1089\/brain.2015.0378","article-title":"The Structural Connectome of the Human Central Homeostatic Network","volume":"6","author":"Edlow","year":"2016","journal-title":"Brain Connect."},{"key":"B28","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1093\/jnen\/nlz062","article-title":"The serotonin brainstem hypothesis for the sudden infant death syndrome","volume":"78","author":"Kinney","year":"2019","journal-title":"J Neuropathol Exp Neurol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"582051","DOI":"10.3389\/fneur.2020.582051","article-title":"Sudden unexplained death in childhood: a neuropathology review","volume":"11","author":"McGuone","year":"2020","journal-title":"Front Neurol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1093\/jnen\/nlz136","article-title":"Neuropathologic changes in sudden unexplained death in childhood","volume":"79","author":"McGuone","year":"2020","journal-title":"J Neuropathol Exp Neurol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/s40478-020-00928-3","article-title":"Hippocampal granule cell dispersion: a non-specific finding in pediatric patients with no history of seizures","volume":"8","author":"Roy","year":"2020","journal-title":"Acta Neuropathol Commun."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/nan.12746","article-title":"Blinded review of hippocampal neuropathology in sudden unexplained death in childhood reveals inconsistent observations and similarities to explained paediatric deaths","author":"Leitner","year":"2021","journal-title":"Neuropathol Appl Neurobiol"},{"key":"B33","first-page":"407","article-title":"The primate serotonergic system: a review of human and animal studies and a report on Macaca fascicularis","volume":"43","author":"Azmitia","year":"1986","journal-title":"Adv Neurol"},{"key":"B34","doi-asserted-by":"crossref","first-page":"189","DOI":"10.55782\/ane-2004-1505","article-title":"Serotonin and neurogenesis in the hippocampal dentate gyrus of adult mammals","volume":"64","author":"Djavadian","year":"2004","journal-title":"Acta Neurobiol Exp."},{"key":"B35","first-page":"661","article-title":"Abnormalities of the hippocampus in sudden and unexpected death in early life","volume-title":"SIDS Sudden Infant and Early Childhood Death: The Past, the Present and the Future.","author":"Kinney","year":"2018"},{"key":"B36","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1212\/01.WNL.0000049930.93113.20","article-title":"PET imaging of 5-HT1A receptor binding in patients with temporal lobe epilepsy","volume":"60","author":"Toczek","year":"2003","journal-title":"Neurology."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1212\/01.WNL.0000123696.98166.AF","article-title":"Limbic reductions of 5-HT1A receptor binding in human temporal lobe epilepsy","volume":"62","author":"Savic","year":"2004","journal-title":"Neurology."},{"key":"B38","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1165\/rcmb.2014-0329OC","article-title":"The alteration of neonatal raphe neurons by prenatal-perinatal nicotine. Meaning for sudden infant death syndrome","volume":"53","author":"Cerpa","year":"2015","journal-title":"Am J Respir Cell Mol Biol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1579","DOI":"10.1152\/japplphysiol.91629.2008","article-title":"Prenatal nicotine-exposure alters fetal autonomic activity and medullary neurotransmitter receptors: implications for sudden infant death syndrome","volume":"107","author":"Duncan","year":"2009","journal-title":"J Appl Physiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2002","DOI":"10.1007\/s12035-019-01854-9","article-title":"Cellular and molecular changes in hippocampal glutamate signaling and alterations in learning, attention, and impulsivity following prenatal nicotine exposure","volume":"57","author":"Polli","year":"2020","journal-title":"Mol Neurobiol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"388","DOI":"10.2174\/1570159X15666170714092436","article-title":"Differential effects of nicotine exposure on the hippocampus across lifespan","volume":"16","author":"Zeid","year":"2018","journal-title":"Curr Neuropharmacol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"e20163334","DOI":"10.1542\/peds.2016-3334","article-title":"Prematurity and sudden unexpected infant deaths in the United States","volume":"140","author":"Ostfeld","year":"2017","journal-title":"Pediatrics."},{"key":"B43","first-page":"15","article-title":"Sudden infant death syndrome: an overview","volume-title":"SIDS Sudden Infant and Early Childhood Death: The Past, the Present and the Future.","author":"Duncan","year":"2018"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2021.762017\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,14]],"date-time":"2024-09-14T22:08:45Z","timestamp":1726351725000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2021.762017\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,21]]},"references-count":43,"alternative-id":["10.3389\/fped.2021.762017"],"URL":"https:\/\/doi.org\/10.3389\/fped.2021.762017","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,21]]},"article-number":"762017"}}