Nicotinic Receptors in the Brainstem Ascending Arousal System in SIDS With Analysis of Pre-natal Exposures to Maternal Smoking and Alcohol in High-Risk Populations of the Safe Passage Study.

Arunnjah Vivekanandarajah,Jhodie R Duncan,Morgan E Nelson,Kevin G Broadbelt,Amy J Elliott,Kathryn Schissler,Theonia K Boyd,William P Fifer,Ingrid A Holm,Johan Dempers,Robin L Haynes,Perri Jacobs,Dan Zaharie,Laura Nelsen,Drucilla J Roberts,Lucy Brink,Rebecca D Folkerth,Jyoti Angal,Colleen A Wright,Jacob Cotton,Hannah C Kinney,Mary Ann Sens,Coen Groenewald,Kristin Mcmillan,Hein J Odendaal,Pawel Schubert,Megan E Minter ,Brad Randall ,Jean Coldrey ,E Geldenhuys ,Michael Myers ,Shabbir Ahmed Wadee ,Hương Thanh Trần ,Elsie Burger

doi:10.3389/fneur.2021.636668

Abstract

Pre-natal exposures to nicotine and alcohol are known risk factors for sudden infant death syndrome (SIDS), the leading cause of post-neonatal infant mortality. Here, we present data on nicotinic receptor binding, as determined by 125I-epibatidine receptor autoradiography, in the brainstems of infants dying of SIDS and of other known causes of death collected from the Safe Passage Study, a prospective, multicenter study with clinical sites in Cape Town, South Africa and 5 United States sites, including 2 American Indian Reservations. We examined 15 pons and medulla regions related to cardiovascular control and arousal in infants dying of SIDS (n = 12) and infants dying from known causes (n = 20, 10 pre-discharge from time of birth, 10 post-discharge). Overall, there was a developmental decrease in 125I-epibatidine binding with increasing postconceptional age in 5 medullary sites [raphe obscurus, gigantocellularis, paragigantocellularis, centralis, and dorsal accessory olive (p = 0.0002–0.03)], three of which are nuclei containing serotonin cells. Comparing SIDS with post-discharge known cause of death (post-KCOD) controls, we found significant decreased binding in SIDS in the nucleus pontis oralis (p = 0.02), a critical component of the cholinergic ascending arousal system of the rostral pons (post-KCOD, 12.1 ± 0.9 fmol/mg and SIDS, 9.1 ± 0.78 fmol/mg). In addition, we found an effect of maternal smoking in SIDS (n = 11) combined with post-KCOD controls (n = 8) on the raphe obscurus (p = 0.01), gigantocellularis (p = 0.02), and the paragigantocellularis (p = 0.002), three medullary sites found in this study to have decreased binding with age and found in previous studies to have abnormal indices of serotonin neurotransmission in SIDS infants. At these sites, 125I-epibatidine binding increased with increasing cigarettes per week. We found no effect of maternal drinking on 125I-epibatidine binding at any site measured. Taken together, these data support changes in nicotinic receptor binding related to development, cause of death, and exposure to maternal cigarette smoking. These data present new evidence in a prospective study supporting the roles of developmental factors, as well as adverse exposure on nicotinic receptors, in serotonergic nuclei of the rostral medulla—a finding that highlights the interwoven and complex relationship between acetylcholine (via nicotinic receptors) and serotonergic neurotransmission in the medulla.

Highlights

The sudden infant death syndrome (SIDS) is a major worldwide public health problem
The causes of death for the control groups are given in Table 1, with demises separated as preor post-discharge, based on whether the infant died in the hospital without being discharged after birth or at home after discharge
Significant difference was only detected in one nucleus, the pontis oralis (PoO), this abnormality represents a deficit in an arousal system that likely places an infant at risk for SIDS

Summary

Introduction

The sudden infant death syndrome (SIDS) is a major worldwide public health problem. It is defined as the sudden death of a seemingly healthy infant under 1 year of age that remains unexplained after a thorough case investigation, including the performance of a complete autopsy, an examination of the death scene, and a review of the infant’s clinical history [1]. The SIDS risk increases in socioeconomically disadvantaged minority populations throughout the world, e.g., African-Americans in the urban United States, American Indians in the Northern Plains, mixed ancestry groups in Cape Town in South Africa, Maoris in New Zealand, and Aboriginal and Torres Strait Islanders in Australia [3,4,5,6,7]. Biological mechanisms in minority high-risk SIDS populations have been historically understudied because of the decreased access to modern forensic centers with pediatric research tools, lack of funds for research in health disparities, and the general mistrust of autopsy by these minority populations [8,9,10]

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