Project II will test the hypothesis In developing rodent models that the underlying """"""""vulnerability"""""""", which contributes to SIDS, is determined by the Interaction between: 1) intrinsic ('pre-existing') deficiencies of the neurotransmitter 5-HT or the 14-3-3 family of regulatory proteins, both of which are abnormal In SIDS cases; and 2) certain prenatal exposures. The prenatal exposures are: a) intermittent hypoxia applied for 3 days at the gestational period of 5-HT neuron emergence, or b) during the first week of postnatal life when rodent pups are Immature (analogous to the last human trimester);c) maternal nicotine exposure;and d) maternal SSRl exposure. The first three prenatal exposures are strongly related to SIDS by epidemiology;the third, maternal SSRIs, less so, but Is of critical interest because of their relatively common use and their effects on 5-HT. We will apply three models of """"""""intrinsic"""""""" brainstem 5-HT deficiency: 1) transgenic mouse pups expressing a novel receptor on 5-HT transporter-positive neurons resulting In llgand-lnducible and reversible suppression of action potential firing in all 5-HT neurons (Slc6a4-cre:RC::PDI), and In a discrete subset of 5- HT neurons derived from rhombomere 5 (r5) (Project IV);2) rat pups from dams fed a diet deficient in tryptophan, shown by us to result In a ~45% decrease in the pups'medullary 5-HT levels;and 3) inhibition of 14-3-3 protein by difopein, a protein Induced by focal Injection of a viral cDNA construct.
In Specific Aim 1, we will determine whether the Interaction between a pre-existing deficiency and a prenatal exposure affects: a) cardiorespiratory responses to repeated bouts of hypoxia, which normally Induce long term facilitation of breathing and to more severe anoxia/asphyxia which result In prolonged apnea and Induce autoresuscitation;b) the laryngeal chemoreflex, which can Induce apnea, and menthol-mediated respiratory inhibition;and c) arousal responses to hypoxia and the development of sleep.
In Specific Aim 2, we explore biomarkers that could be applied to Identify infants at risk. Including alterations in serum 5-HT and heart rate variability.
In Specific Aim 3, we Investigate potential treatments. Including tryptophan supplementation and caffeine, a cardiorespiratory stimulant.

Public Health Relevance

Project II focusses on physiological events In early development that could contribute to mortality In rodent models that by design mimic the combinations of: a) pathological abnormalities found In brainstems of SIDS cases;and b) 'prenatal'stresses defined by epidemiology. The relevance Is In defining mechanisms that link human neuropathology to physiological dysfunction that can cause death In an age-specific manner.

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 #
8739292
Study Section
Special Emphasis Panel (ZHD1-DSR-Z)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
17
Fiscal Year
2014
Total Cost
$493,421
Indirect Cost
$65,628
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

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