VENTILATORY ACTIVITY IN EUPNEA AND GASPING IN THE MEDULLARY SEROTONERGIC SYSTEM

Boston Children'S Hospital, Boston MA

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Abstract

The overall hypothesis of this program project is that a neurological subset of SIDS cases is due to developmental abnormalities in the medullary 5-HT system that interfere with protective homeostatic responses to potentially life-threatening but open occurring events during sleep, such as hypoxia, hypercarbia, asphyxia, hyperthermia, blood pressure changes, and/or reflex apnea. We proposed that the sudden infant death syndrome (SIDS) results when an infant with a neuronal vulnerability is exposed to an exogenous stressor at a critical time in development ("The Triple Risk Model"). All of the studies conducted to date under the auspices of the Program Project Grant remain consistent with this hypothesis. We have accumulated evidence that quite modest disruption of the piglet homologue of the arcuate nucleus diminishes ventilatory responses to hypercapnia and hypoxia, diminishes protective cardiorespiratory responses and permits unfettered action of stimuli that inhibit respiration. To date, we have used relatively non-specific inhibitors of neural function within the rostroventral medulla (RVM) and caudal raphe; these regions are homologous with the arcuate nucleus. However, the deficits in neurotransmitter receptors in infants dying of SIDS are quite specific, with a lack of muscarinic, kainate and serotonin receptors in a subset of SIDS infants. Among these neurotransmitters, we believe that serotonin is of paramount importance, and the action of the medullary serotonergic neurons promotes cardiorespiratory stability. Prenatal exposure to cigarette smoking is well recognized as a risk factor in the SIDS. It is our hypothesis that nicotine disrupts the development or function of medullary serotonergic neurons and thereby contributes to the vulnerability to exogenous stressors that may underlie SIDS. The goals of our future studies will be to study the mechanisms whereby the medullary serotonergic system influences a variety of respiratory functions. We will study the role of serotonin in eupnea and gasping and in the respiratory responses of nerves to muscles of the upper airway and diaphragm. We will test responses to excitatory stimuli, such as hypercapnia, and inhibitory stimuli, such as baroreceptor activation and stimulation of the superior laryngeal nerve and trigeminal nerve. The importance of serotonergic mechanisms will be assessed using a combination of focal application of agonists and antagonists and recordings of single unit activity within these regions. Similar studies will be performed in animals with and without prenatal exposure to nicotine. All studies will be performed in a unique preparation: the perfused decerebrate heart-brainstem of the neonatal or juvenile rat.