Acute manipulation of serotonergic neurons alters the mouse neonatal response to homeostatic stressors.

Many sudden infant death syndrome (SIDS) cases are associated medullary serotonergic (5‐HT) neuron abnormalities. We hypothesize that these abnormalities impair infants from adequately responding to stressors, such as hypoxia and hypercapnia (asphyxia). In response to asphyxia, young mammals initiate the “autoresuscitation” reflex – a survival promoting mechanism aimed at restoring homeostasis. Deficiency in this reflex is a proposed mechanism for SIDS mortality. To test the acute role of 5‐HT neurons in autoresuscitation, we applied a chemogenetic neuronal inhibition strategy to inducibly suppress the activity of 5‐HT neurons in unanesthetized mouse pups. Specifically, we expressed the synthetic inhibitory G‐protein coupled receptor, Di, selectively in 5‐HT neurons using mice transgenic for the driver Pet1::Flpe and the conditional Di‐expressing knock‐in allele RC::FDi . Selective 5‐HT neuron inhibition follows upon intraperitoneal CNO injection. Using head‐out plethysmography, we measured cardiorespiratory responses to repeated episodes of anoxia‐induced (97% N 2 /3% CO 2 ) apnea following acute inhibition of 5‐HT neuron activity in P8 mouse pups. After injection with CNO, Di‐expressing pups, but not controls, exhibited altered homeostatic parameters prior to an anoxic challenge. Additionally failure to autoresuscitate after anoxic challenge was more pronounced in CNO/Di‐triggered pups than in controls, and was associated with a longer time to restore homeostasis. Results suggest that acute suppression of 5‐HT neuron firing in mouse pups leads to altered baseline cardiorespiratory homeostasis and abnormal cardiorespiratory recovery from anoxia.