The sudden infant death syndrome (SIDS) is the sudden death of an infant that remains unexplained after a complete review of the history, autopsy, and death scene investigation;it is the leading cause of postneonatal infant mortality in the United States today. Based upon our findings to date, we hypothesize that SIDS is due to an underlying abnormality in the medullary homeostatic network that: 1) results in a failure of protective responses to life-threatening stressors during sleep in a critical developmental period; and 2) importantly involves serotonin (5-hydroxytryptamine, 5-HT), y-aminobutyric acid (GABA), and their potential interactions with other neurotransmitter systems and the signal transduction family 14-3-3. Initiated in 1998, our program brings together a highly committed group of 23 investigators and their trainees to address the potential role of the brain in SIDS. Located at 3 medical institutions across the country and the medical examiner's system in San Diego, CA, we bring to bear upon the SIDS problem outstanding expertise in multiple clinical and scientific disciplines in 3 integrated projects and 2 cores (Administrativ and Neuroanatomy). The 7 inter-related themes proposed for investigation with state-of-the-art methodologies in the next (fourth) cycle are: 1) gene expression profiles of the medullary homeostatic network in SIDS infants and animal models (Projects I and II;2) the interaction of prenatal exposures (hypoxia and nicotine) with preexisting 5-HT dysfunction that potentially leads to homeostatic impairment in the postnatal period (Projects II and III);3) the mechanism(s) of physiological derangements in protective homeostatic responses related to 5-HT and GABA, including autoresuscitation, arousal, and the laryngeal chemoreflex (Projects II and III);4) the development and connectivity of subtypes of brainstem 5-HT neurons related to different homeostatic functions (Projects III);5) a potential link between abnormalities in the caudal/rostral 5-HT domains of the brainstem and hippocampal targets in SIDS brains (Project I);6) treatment of abnormalities in animal models with specific drugs (Project II);and 7) the development of future biomarkers of brainstem pathology in SIDS infants.

Public Health Relevance

The determination of the cause(s) and mechanism(s) of SIDS, as sought in this program, is the essential step towards developing specific biomarkers and therapies for infants at risk to prevent all SIDS deaths. A critical strength of the program is its demonstrated capacity to integrate human and animal studies that inform and expand upon each other. In essence, there is no other scientific group in the United States that is investigating the neural basis of SIDS in such a cohesive, synergistic, stable, and productive way.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD036379-17
Application #
8739289
Study Section
Special Emphasis Panel (ZHD1-DSR-Z (KH))
Program Officer
Willinger, Marian
Project Start
1998-04-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
17
Fiscal Year
2014
Total Cost
$1,595,716
Indirect Cost
$328,140
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Edlow, Brian L; McNab, Jennifer A; Witzel, Thomas et al. (2016) The Structural Connectome of the Human Central Homeostatic Network. Brain Connect 6:187-200
Hefti, Marco M; Kinney, Hannah C; Cryan, Jane B et al. (2016) 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. Forensic Sci Med Pathol 12:4-13
Commons, Kathryn G (2016) Ascending serotonin neuron diversity under two umbrellas. Brain Struct Funct 221:3347-60
Goodstein, M H; Hauck, F R; Darnall, R A et al. (2016) Swaddling is not contraindicated in the newborn period. J Perinatol 36:160
Barrett, Karlene T; Dosumu-Johnson, Ryan T; Daubenspeck, J Andrew et al. (2016) Partial Raphe Dysfunction in Neurotransmission Is Sufficient to Increase Mortality after Anoxic Exposures in Mice at a Critical Period in Postnatal Development. J Neurosci 36:3943-53
Richerson, George B; Boison, Detlev; Faingold, Carl L et al. (2016) From unwitnessed fatality to witnessed rescue: Pharmacologic intervention in sudden unexpected death in epilepsy. Epilepsia 57 Suppl 1:35-45
Cerpa, Veronica J; Wu, Yuanming; Bravo, Eduardo et al. (2016) Medullary 5-HT neurons: Switch from tonic respiratory drive to chemoreception during postnatal development. Neuroscience :
Darnall, Robert A; Schneider, Robert W; Tobia, Christine M et al. (2016) Eliminating medullary 5-HT neurons delays arousal and decreases the respiratory response to repeated episodes of hypoxia in neonatal rat pups. J Appl Physiol (1985) 120:514-25
Goldstein, Richard D; Trachtenberg, Felicia L; Sens, Mary Ann et al. (2016) Overall Postneonatal Mortality and Rates of SIDS. Pediatrics 137:
Hefti, Marco M; Cryan, Jane B; Haas, Elisabeth A et al. (2016) Hippocampal malformation associated with sudden death in early childhood: a neuropathologic study: Part 2 of the investigations of The San Diego SUDC Research Project. Forensic Sci Med Pathol 12:14-25

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