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
Darnall, Robert A; Chen, Xi; Nemani, Krishnamurthy V et al. (2017) Early postnatal exposure to intermittent hypoxia in rodents is proinflammatory, impairs white matter integrity, and alters brain metabolism. Pediatr Res 82:164-172
Panzini, Chris M; Ehlinger, Daniel G; Alchahin, Adele M et al. (2017) 16p11.2 deletion syndrome mice perseverate with active coping response to acute stress - rescue by blocking 5-HT2A receptors. J Neurochem 143:708-721
Ehlinger, Daniel G; Commons, Kathryn G (2017) Altered Cav1.2 function in the Timothy syndrome mouse model produces ascending serotonergic abnormalities. Eur J Neurosci 46:2416-2425
Commons, Kathryn G; Cholanians, Aram B; Babb, Jessica A et al. (2017) The Rodent Forced Swim Test Measures Stress-Coping Strategy, Not Depression-like Behavior. ACS Chem Neurosci 8:955-960
Cerpa, Veronica J; Wu, Yuanming; Bravo, Eduardo et al. (2017) Medullary 5-HT neurons: Switch from tonic respiratory drive to chemoreception during postnatal development. Neuroscience 344:1-14
Haynes, Robin L; Frelinger 3rd, Andrew L; Giles, Emma K et al. (2017) High serum serotonin in sudden infant death syndrome. Proc Natl Acad Sci U S A 114:7695-7700
Tenpenny, Richard C; Commons, Kathryn G (2017) What Gene Mutations Affect Serotonin in Mice? ACS Chem Neurosci 8:987-995
Hennessy, Morgan L; Corcoran, Andrea E; Brust, Rachael D et al. (2017) Activity of Tachykinin1-Expressing Pet1 Raphe Neurons Modulates the Respiratory Chemoreflex. J Neurosci 37:1807-1819
Guo, Yue-Ping; Commons, Kathryn G (2017) Serotonin neuron abnormalities in the BTBR mouse model of autism. Autism Res 10:66-77
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

Showing the most recent 10 out of 142 publications