Loss of Htr1B leads to a failure in the neonate autoresuscitation reflex

Sudden Infant Death Syndrome (SIDS) is the leading cause of death in infants under the age of one and takes the lives of 1,500 infants per year in the US alone, comprising half of all Sudden Unexpected Infant Death Cases. While the etiology of SIDS is unknown, a leading hypothesis is the triple risk model, which states that an infant with an innate vulnerability is challenged with an exogenous stressor during a critical developmental period (typically defined as the first year of life) which results in a SIDS case. Many SIDS cases are thought to be mechanistically driven by a failure in the autoresuscitation reflex. The autoresuscitation reflex is initiated by severe hypoxic conditions, which consists of a series of gasps to revitalize cardiorespiratory function following apnea and bradycardia. The failure of this reflex is poorly understood, but post-mortem studies have found a reduction of central serotonin (5-HT) and reduced binding of several 5-HT receptors. As 5-HT is an established chemoreception network and causal studies in animal models demonstrate significant vulnerabilities in neonatal animals during a SIDS-like assay that tests the autoresuscitation reflex, 5-HT is likely central in SIDS outcomes. What remains to be understood is the cellular and molecular mechanisms through which 5-HT plays a role in the autoresuscitation reflex and how those mechanisms may be disrupted in SIDS. With this identified as a primary target, we also investigated the potential for caffeine, an established therapeutic in NICU infants with poor respiratory development, as a potential therapeutic intervention in these models. We hypothesize that 5-HT1B is required for successful autoresuscitation and that this perturbation may be rescued with caffeine. 5-HT1B is known for its role as a pre-synaptic autoreceptor, on serotonin neurons, mediating the release of serotonin into the synapse. Additionally, the receptor is expressed throughout the central nervous system as well as the cardiopulmonary system making this receptor a likely candidate that is important for autoresuscitation. To test this hypothesis, we utilized our automated closed-loop robotic platform for neonate cardiorespiratory measurements (Looper) to assay P7 Htr1B genetic loss of function (Htr1B-/-) mice in a SIDS-like assay, examining their abilities to survive repeated anoxic gas challenges, mimicking unsafe sleep environments, to test the autoresuscitation reflex. Htr1B-/- mice show decreased survival to repeated anoxic challenges compared to Htr1B+/+ littermate controls, independent of sex. Htr1B-/- mice also experience uncoordinated cardiorespiratory recovery, primarily following the initial anoxic challenge. Conditional loss of Htr1B on 5-HT neurons had no effect, suggesting the role for this receptor in autoresuscitation success is likely mediated at a postsynaptic location. Importantly, caffeine pre-treatment, commonly used for treatment in the NICU, reversed Htr1B-/- mice survival to control levels and reestablished proper cardiorespiratory coordination for recovery. Future studies will investigate perturbations in neuronal activity caused by the loss of Htr1B in the autoresuscitation response and determining which post-synaptic locations require its expression. F31HL168962-01A1, PRE241194092 (01/2024 – 09/2024), NIH/NHLBI R01HLN161142-01 and R01HL130249-07 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.