Concurrent, dual perturbations of the 5-HT and NA systems reveal dynamic interplay in regulating the neonate autoresuscitation reflex

Sudden Infant Death Syndrome (SIDS) is a leading cause of infant mortality worldwide. Failure of the neonate auto-resuscitation reflex is hypothesized to be a common endpoint in many SIDS cases. Although SIDS is idiopathic, postmortem studies indicate abnormalities in the serotonergic (5-HT) and noradrenergic (NA) systems of the respiratory network. To better understand the contributions and interactions of these two systems in autoresuscitation, we combined a novel series of Cre- and FLPo- recombinase driver mouse lines and conditional inhibitory and excitatory DREADD lines for singular excitation or inhibition of either the whole 5-HT or whole NA systems. These models were then uniquely combined to further enable 1) concurrent excitation or inhibition of both systems in the same neonate or 2) inhibition of one system while exciting the other system in the same neonate. In total, we developed 8 distinct sets of conditional genetic mouse models for singular and combined 5-HT and NA system perturbation paradigms. The 8 experimental groups and 2 control groups were repeatedly assayed for the autoresuscitation reflex using a robotic neonate cardiorespiratory assessment platform, Looper. Neonates are repeatedly tested until they succumb. Resulting data were analyzed with our recently published waveform analysis software, Breathe Easy, to calculate operant outcomes. In 320 mice total, we found 4 groups with decreased autoresuscitation success: NA activation, NA activation + 5-HT activation, NA activation + 5-HT inhibition, and 5-HT activation. There was no change in survival in any of the other groups including 5-HT inhibition. Preliminary results suggest a potential cardiovascular mechanism of autoresuscitation failure independent of respiratory outcomes. At baseline, all 4 groups with decreased survival showed increased heart rate (HR) whereas the other groups either had the same HR or a decreased HR. During early recovery, defined as beginning at the 10 th breath following the primary gasp until recovery, the 4 groups with decreased survival show higher HR than the other groups following the 1 st bout of autoresuscitation. As recovery progressed in these groups, HR continued to increase as well until the next autoresuscitation test. Ventilatory frequency, tidal volume, and ventilation all increased in the 3 groups where NA was activated either in isolation or in combination, but there were decreases in all other groups, including 5-HT activation. As the underlying genetic and environmental mechanisms driving SIDS are likely to have pleiotropic effects across multiple neural systems, our first-of-its-kind dual 5-HT and NA system modulations set the stage to more comprehensively model key aspects of SIDS neuropathology that reveal a previously uncharacterized dynamic functional interplay between the NA and 5-HT systems in protective respiratory reflexes. NIH: 1F32HL160073-01A1, R01HL130249 44617-S4. BCM McNair Scholar Program, March of Dimes Basil O'Connor Research Award, Parker B. Francis Fellowship, CJ Foundation for SIDS. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.