Arousal is a vital protective mechanism in infants when confronted with potentially life-threatening hypoxia during sleep?whether from airway obstruction, rebreathing, apnea, or circulatory failure. Our focus is on the descending, or subcortical, arousal pathways that modulate breathing, spinal motor activity, and sympathetic activity that controls body temperature, heart rate, and blood pressure. We now know that 70% of SIDS infants have decreased 5-HT1A receptor and serotonin transporter (5-HTT) binding, expressed per 5-HT neuron, and increased numbers of 5-HT neurons, in medullary regions important for modulating arousal, motor activity, body temperature, heart rate, and breathing. Medullary 5-HT neurons also receive excitatory orexinergic and inhibitory GABAergic inputs that by themselves have important roles in arousal. We propose that SIDS infants are at risk because of abnormalities in medullary serotonergic (5-HT) function that lead to altered modulation of descending pathways essential for coordinated and effective arousal, and that death results from a combination of impaired arousal mechanisms and extrinsic stressors that occurs during a critical stage of development and typically during sleep. In the analysis of defective arousal mechanisms in SIDS, it is important to consider that many SIDS infants have repeated episodes of apnea and hypoxia in the days or weeks prior to death. We propose that repeated exposure to subclinicai hypoxia leads to arousal habituation. Habituation refers to the waning over time of a physiological response to repetitive stimuli in order to prevent inappropriate responses to non-dangerous or non-important stimuli?yet """"""""habituation"""""""" of arousal from sleep to a dangerous stimulus such as severe intermittent hypoxia could lead to disastrous consequences. In this project, we will define the characteristics of subcortical arousals during development in the rat and test the novel hypothesis that excessive habituation is a major contributor to dysfunctional arousals. We will further determine whether effective arousal from sleep in response to hypoxia is affected by the manipulation of the 5-HT1A and GABAA receptor and the 5-HTT, chronic exposure to intermittent hypoxia, overheating and fever, and prenatal exposure to tobacco smoke. Our focus upon the poorly understood function, pathophysiology, and neuroanatomy of subcortical arousal, including its interaction with thermoregulation, is a major strength of this project. The results of these studies will provide key information about the role of serotonin in arousal mechanisms and identify important links between intermittent exposure to hypoxia, serotonin, arousal, and SIDS. This information will be critical and lead toward ultimately understanding the pathophysiological mechanisms of SIDS and developing therapeutic interventions to eradicate all SIDS deaths.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD036379-15
Application #
8376687
Study Section
Special Emphasis Panel (ZHD1-MCHG-B)
Project Start
Project End
2013-09-23
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
15
Fiscal Year
2012
Total Cost
$310,685
Indirect Cost
$23,191
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

Showing the most recent 10 out of 125 publications