No abstract

The serotonergic (5-HT) system in the human medulla oblongata is well-recognized to play an important role in the regulation of respiratory and autonomic function. In this study, using both immunocytochemistry (n=5) and tissue section autoradiography with the radioligand 125 I-1-(2,5-dimethoxy-4-iodo-phenyl)2-aminopropane (n=7), we examine the normative development and distribution of the 5-HT 2A receptor in the human medulla during the last part of gestation and first postnatal year when dramatic changes are known to occur in respiratory and autonomic control, in part mediated by the 5-HT 2A receptor. High 5-HT 2A receptor binding was observed in the dorsal motor nucleus of the vagus (preganglionic parasympathetic output) and hypoglossal nucleus (airway patency); intermediate binding was present in the nucleus of the solitary tract (visceral sensory input), gigantocellularis, intermediate reticular zone, and paragigantocellularis lateralis. Negligible binding was present in the raphé obscurus and arcuate nucleus. The pattern of 5-HT 2A immunoreactivity paralleled that of binding density. By 15 gestational weeks, the relative distribution of the 5-HT 2A receptor was similar to that in infancy. In all nuclei sampled, 5-HT 2A receptor binding increased with age, with significant increases in the hypoglossal nucleus (p=0.027), principal inferior olive (p=0.044), and medial accessory olive (0.038). Thus, 5-HT 2A receptors are concentrated in regions involved in autonomic and respiratory control in the human infant medulla, and their developmental profile changes over the first year of life in the hypoglossal nucleus critical to airway patency and the inferior olivary complex essential to cerebellar function.

The sudden infant death syndrome (SIDS), the leading cause of postneonatal infant mortality in the United States, is typically associated with a sleep period. Previously, we showed evidence of serotonergic abnormalities in the medulla (e.g. altered serotonin (5-HT)1A receptor binding), in SIDS cases. In rodents, 5-HT2A/C receptor signaling contributes to arousal and autoresuscitation, protecting brain oxygen status during sleep. Nonetheless, the role of 5-HT2A/C receptors in the pathophysiology of SIDS is unclear. We hypothesize that in SIDS, 5-HT2A/C receptor binding is altered in medullary nuclei that are key for arousal and autoresuscitation. Here, we report altered 5-HT2A/C binding in several key medullary nuclei in SIDS cases (n = 58) compared to controls (n = 12). In some nuclei the reduced 5-HT2A/C and 5-HT1A binding overlapped, suggesting abnormal 5-HT receptor interactions. The data presented here (Part 1) suggest that a subset of SIDS is due in part to abnormal 5-HT2A/C and 5-HT1A signaling across multiple medullary nuclei vital for arousal and autoresuscitation. In Part II to follow, we highlight 8 medullary subnetworks with altered 5-HT receptor binding in SIDS. We propose the existence of an integrative brainstem network that fails to facilitate arousal and/or autoresuscitation in SIDS cases.

The 5‐HT system in the medulla oblongata plays an important role in the regulation of homeostatic function. Previously, we identified multiple 5‐HT abnormalities in the medulla in SIDS infants, including a significant reduction in 5‐HT1A receptor binding. The question remains whether the expression of other 5‐HT receptor subtypes are abnormal in SIDS. As a first step towards answering this question, we mapped the distribution of the 5‐HT2A receptor in normative human infant medulla using tissue section autoradiography with 86.3pM 125I DOI (n=5) and immunocytochemistry with goat polyclonal antibody at a 1:100 dilution (n=4). The 5‐HT2A receptor plays important roles in 5‐HT‐mediated cardiorespiratory functions in animals, including firing of preBötzinger Complex neurons. High 5‐HT2A receptor binding was observed in the dorsal motor nucleus of the vagus, hypoglossal nucleus and olivary complex; intermediate binding was present in the nucleus of the solitary tract and paragigantocellularis lateralis; low binding was detected in the arcuate nucleus and raphé. The pattern of 5‐HT2A immunostaining was consistent with that of binding. These observations indicate that 5‐HT2A receptors localize to medullary regions concerned with cardiorespiratory function in the human infant, and underscore their importance in the analysis of the medullary 5‐HT hypothesis in SIDS. Support: NICHD (R37‐HD20991, PO1‐HD36379), CJ Murphy Foundation