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
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