Developmental alterations of the respiratory human retrotrapezoid nucleus in sudden unexplained fetal and infant death

Lavezzi, Anna Maria; Weese‐Mayer, Debra E.; Yu, Margaret Y.; Jennings, Lawrence J.; Corna, Melissa F.; Casale, Valentina; Oneda, Roberta; Matturri, Luigi

doi:10.1016/j.autneu.2012.06.005

Cited by 47 publications

(45 citation statements)

References 40 publications

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“…The brainstem cholinergic system, the RTN, peripheral chemoreceptors and brainstem serotonergic neurons have been judged abnormal in some cases of SIDS (Duncan et al, 2010; Lavezzi et al, 2012; Pena et al, 2004; Porzionato et al, 2013) but defects of the serotonergic system may be most critical. Transgenic mice lacking serotonin neurons have high mortality during development, severe neonatal apneas (Hodges et al, 2009) and fail to arouse when exposed to CO 2 (Buchanan and Richerson, 2010).…”

Section: Serotonergic Neurons and Sudden Infant Death Syndrome (Sids)mentioning

confidence: 99%

Neural Control of Breathing and CO2 Homeostasis

Guyenet

Bayliss

2015

Neuron

391

332

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Summary Recent advances have clarified how the brain detects CO2 to regulate breathing (central respiratory chemoreception). These mechanisms are reviewed and their significance is presented in the general context of CO2/pH homeostasis through breathing. At rest, respiratory chemoreflexes initiated at peripheral and central sites mediate rapid stabilization of arterial PCO2 and pH. Specific brainstem neurons (e.g., retrotrapezoid nucleus, RTN; serotonergic) are activated by PCO2 and stimulate breathing. RTN neurons detect CO2 via intrinsic proton receptors (TASK-2, GPR4), synaptic input from peripheral chemoreceptors and signals from astrocytes. Respiratory chemoreflexes are arousal state-dependent whereas chemoreceptor stimulation produces arousal. When abnormal, these interactions lead to sleep-disordered breathing. During exercise, “central command” and reflexes from exercising muscles produce the breathing stimulation required to maintain arterial PCO2 and pH despite elevated metabolic activity. The neural circuits underlying central command and muscle afferent control of breathing remain elusive and represent a fertile area for future investigation.

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Section: Serotonergic Neurons and Sudden Infant Death Syndrome (Sids)mentioning

confidence: 99%

Neural Control of Breathing and CO2 Homeostasis

Guyenet

Bayliss

2015

Neuron

391

332

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“…Since CNS serotonergic neurons are required for CO 2 -induced arousal in mice (49, 64), the collective evidence suggests that a defect in the development of the serotonergic system in man could perhaps contribute to the failure to arouse or to resuscitate via gasping and therefore to SIDS. Other brain regions or transmitters (e.g., cholinergic system, RTN) have also been found to be abnormal in SIDS (230, 336). …”

Section: Sids Central Oxygen Sensing Gasping and Autoresuscitationmentioning

confidence: 99%

Regulation of Breathing and Autonomic Outflows by Chemoreceptors

Guyenet

2014

Comprehensive Physiology

274

293

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Lung ventilation fluctuates widely with behavior but arterial PCO2 remains stable. Under normal conditions, the chemoreflexes contribute to PaCO2 stability by producing small corrective cardiorespiratory adjustments mediated by lower brainstem circuits. Carotid body (CB) information reaches the respiratory pattern generator (RPG) via nucleus solitarius (NTS) glutamatergic neurons which also target rostral ventrolateral medulla (RVLM) presympathetic neurons thereby raising sympathetic nerve activity (SNA). Chemoreceptors also regulate presympathetic neurons and cardiovagal preganglionic neurons indirectly via inputs from the RPG. Secondary effects of chemoreceptors on the autonomic outflows result from changes in lung stretch afferent and baroreceptor activity. Central respiratory chemosensitivity is caused by direct effects of acid on neurons and indirect effects of CO2 via astrocytes. Central respiratory chemoreceptors are not definitively identified but the retrotrapezoid nucleus (RTN) is a particularly strong candidate. The absence of RTN likely causes severe central apneas in congenital central hypoventilation syndrome. Like other stressors, intense chemosensory stimuli produce arousal and activate circuits that are wake- or attention-promoting. Such pathways (e.g., locus coeruleus, raphe, and orexin system) modulate the chemoreflexes in a state-dependent manner and their activation by strong chemosensory stimuli intensifies these reflexes. In essential hypertension, obstructive sleep apnea and congestive heart failure, chronically elevated CB afferent activity contributes to raising SNA but breathing is unchanged or becomes periodic (severe CHF). Extreme CNS hypoxia produces a stereotyped cardiorespiratory response (gasping, increased SNA). The effects of these various pathologies on brainstem cardiorespiratory networks are discussed, special consideration being given to the interactions between central and peripheral chemoreflexes.

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“…Immunohistochemical expression of Phox2b neurons inside the caudal pons points out the developmental abnormalities of the human RTN (Table 1). It may acutely affect the chemoreception control, thus, performing a vital part in the pathogenesis of SIUDS and SIDS (46). …”

Section: Brainstem Control Of Respiration During the Transition From mentioning

confidence: 99%

Towards Better Understanding of the Pathogenesis of Neuronal Respiratory Network in Sudden Perinatal Death

et al. 2017

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Sudden perinatal death that includes the victims of sudden infant death syndrome, sudden intrauterine death syndrome, and stillbirth are heartbreaking events in the life of parents. Most of the studies about sudden perinatal death were reported from Italy, highlighting two main etiological factors: prone sleeping position and smoking. Other probable contributory factors are prematurity, male gender, lack of breastfeeding, respiratory tract infections, use of pacifiers, infant botulism, extensive use of pesticides and insecticides, etc. However, extensive studies across the world are required to establish the role of these factors in a different subset of populations. Previous studies confirmed the widely accepted hypothesis that neuropathology of the brainstem is one of the main cause of sudden perinatal death. This study is an effort to summarize the neuropathological evaluation of the brainstems and their association to sudden perinatal death. Brainstem nuclei in vulnerable infants undergo certain changes that may alter the sleep arousal cycle, cardiorespiratory control, and ultimately culminate in death. This review focuses on the roles of different brainstem nuclei, their pathologies, and the established facts in this regard in terms of it’s link to such deaths. This study will also help to understand the role of brainstem nuclei in controlling the cardiorespiratory cycles in sudden perinatal death and may provide a better understanding to resolve the mystery of these deaths in future. It is also found that a global initiative to deal with perinatal death is required to facilitate the diagnosis and prevention in developed and as well as developing countries.

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Developmental alterations of the respiratory human retrotrapezoid nucleus in sudden unexplained fetal and infant death

Cited by 47 publications

References 40 publications

Neural Control of Breathing and CO2 Homeostasis

Neural Control of Breathing and CO2 Homeostasis

Regulation of Breathing and Autonomic Outflows by Chemoreceptors

Towards Better Understanding of the Pathogenesis of Neuronal Respiratory Network in Sudden Perinatal Death

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