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.
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