SIDS, failed autoresuscitation, and a novel serotonergic brainstem-cerebellar circuit

The Sudden Infant Death Syndrome (SIDS) remains the leading cause of death in the post-neonatal period. Rare traces from infants who died of SIDS indicate cardiovascular collapse during autoresuscitation, the integrated cardiovascular and sympathetic response necessary to sustain life in severely hypoxic conditions. There is evidence of serotonergic dysfunction in SIDS, including reduced serotonin (5-HT) and reduced 5- HT2A receptors across multiple regions necessary for autoresuscitation. Most SIDS infants have reduced 5- HT2A receptors within the nucleus of the solitary tract (NTS) and medial accessory olive (MAO). Along with the fastigial nucleus of the cerebellum (FN), the NTS and MAO are key components of a brainstem-cerebellar circuit that increases drive to the rostral ventrolateral medulla (RVLM). Ultimately, the activation of the NTS- MAO-FN-RVLM circuit augments sympathetic activity, a response necessary for heart rate and blood pressure recovery from severe hypoxia. The MAO is the sole source of climbing fibers to Purkinje cells (PCs); the latter provide critical neuromodulation to the FN. Prenatal and/or postnatal intermittent hypoxia (IH) are associated with key risk factors for SIDS. IH may compromise autoresuscitation by inducing damage to vulnerable MAO and PCs while also reducing 5-HT2A activity across the entire circuit. Our overarching hypothesis is that an important subset of SIDS infants has reduced drive through 5-HT2A receptors within the NTS-MAO-FN- RVLM circuit. Prenatal or postnatal IH damages the MAO, PC cells, and reduces serotonergic function, compromising the ability of the circuit to restore blood pressure during autoresuscitation, resulting in sudden death. To test these hypotheses, we use a combination of delicate DREAD- and pharmacological- based experiments that manipulate serotonergic inputs to the NTS-MAO-FN-RVLM in infant rats, assessing the extent that drive through 5-HT2A receptors is necessary and sufficient for cardiovascular recovery and survival during autoresuscitation. Rodent studies run in parallel with studies using tissue from SIDS infants and controls. For the first time we examine 5-HT receptor binding and expression in the cerebellum, as well as the integrity of PCs and climbing fibers in SIDS versus controls. The proposed studies are innovative experimentally and conceptually – in particular, the cerebellum's role in successful cardiovascular recovery in autoresuscitation has never been tested experimentally. We pair rodent and human studies to maximize the potential for translational outcomes and clinical impact. From our studies will emerge a new concept that reduced drive through 5-HT2A receptors within a key brainstem-cerebellar circuit underlies a significant proportion of SIDS deaths. The knowledge generated will potentiate the development of key biomarkers and prophylactic strategies to reduce SIDS incidence worldwide. This research therefore aligns with the mission of the National Heart Lung and Blood Institute to support research promoting the prevention and treatment of heart, lung, and blood diseases to enhance the health of all individuals.