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.
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.
|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