The Pendulum Between Breath and Death: Serotonin and Noradrenaline

Sudden Infant Death Syndrome (SIDS) remains a leading cause of infant mortality worldwide. Failure of the neonate autoresuscitation reflex is hypothesized to be a common endpoint in many SIDS cases, often linked to abnormalities in the serotonergic (5-HT) and noradrenergic (NA) systems of the respiratory network. This reflex was tested in a SIDS-like assay consisting of repeated bouts of exposure to an anoxic gas to induce bradycardia and apnea, followed by the restoration of room air to observe successful or failed autoresuscitation. This loop was repeated until autoresuscitation was no longer successful. This study employs innovative conditionally expressed inhibitory (hM4De) and excitatory (hM3D) DREADD models to understand the contributions and interactions of these two neurotransmitter systems in SIDS pathology. Using Cre and FLPo drivers, we created models allowing singular excitation or inhibition of the 5-HT or NA systems. These models were also combined to enable concurrent excitation or inhibition of both systems in the same animal or inhibition of one system and excitation of the other. After two years of complex breeding, combining three loci and six alleles, we developed eight distinct sets of conditional genetic mouse models for various perturbation paradigms of the 5-HT and NA systems. The eight experimental and two control groups were assessed using Looper, a new closed-loop robotic neonate cardiorespiratory assessment platform. Our comprehensive respiratory analysis platform analyzed outcomes, Breathe Easy. Controls used for comparison were CNO-injected, as we also observed an effect of CNO on survival. In 876 mice, we found five groups with decreased survival: NA activation alone, NA activation with 5-HT activation, NA activation with 5-HT inhibition, NA inhibition with 5-HT activation, and, interestingly, 5-HT activation alone. No change in survival was observed in any of the other groups, including those with 5-HT inhibition. At baseline, the five groups with decreased survival showed increased heart rates, while controls and groups with no change in survival either stayed the same or decreased. Ventilatory frequency, tidal volume, and ventilation increased in the three groups with NA activation but decreased in all other groups, including those with 5-HT activation. An apparent cardiac phenotype was observed during early recovery, where the five groups with decreased survival exhibited higher heart rates. Additionally, there appeared to be a unique relationship between heart rates during early versus late recovery in the groups with reduced survival. Our first-of-its-kind dual 5-HT and NA system modulations reveal a previously uncharacterized dynamic functional interplay between these systems in protective respiratory reflexes, setting the stage for a more comprehensive understanding of SIDS neuropathology. NIH (Lusk): 1F32HL160073, R01HL130249 44617-S4. NIH/NHLBI (Ray): R01HLN161142, and R01HL130249.125% This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.