VENTRAL MEDULLA, BREATHING, AND CENTRAL CHEMORECEPTION

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We proposed that SIDS results from abnormalities in the ventral medulla that interfere with normal protective cardiorespiratory reflexes. In this project we shall disrupt experimentally in piglets, at two developmental times, the homologue of the human arcuate nucleus found to be abnormal in SIDS victims. This homologue is proposed to contain the retrotrapezoid nucleus (RTN) and parapyramidal regions, the medullary raphe region, and the central chemoreceptor regions of the caudal ventrolateral medulla. In adult animals, disruption of the RTN/parapyramidal and raphe regions is known to diminish respiratory output and the sensitivity of the respiratory response to increased carbon dioxide. The magnitude of the effects is greater in anesthesia. Denervation of peripheral chemoreceptors magnifies the deleterious effects of this disruption in adult animals; when performed in newborn animals with intact brainstem function, it results in hypoventilation, more frequent apneas, and death. We shall, in the decerebrate piglet with and without intact carotid bodies, alter arcuate homologue function by microinjection of 1) an excitatory amino acid neurotoxin to produce lesions, and 2) muscarinic and ionotropic glutamate agonists/antagonists, and thyrotropin releasing-hormone. Phrenic nerve output and blood pressure in the baseline state and their responses to hypercapnia and asphyxia will be measured. In the unanesthetized chronic piglet preparations with and without intact carotid bodies, we will examine the effect of arcuate homologue lesions on breathing and blood pressure during natural wakefulness and sleep and on the responses to hypercapnia and asphyxia. Our goal is to examine the relative roles of arcuate homologue neurons and carotid body inputs on breathing and blood pressure in the absence of anesthesia and in natural sleep and wakefulness. In respect to the Triple Risk Model for SIDS pathogenesis, we are 1) experimentally creating a vulnerability by means of our lesions or injections, at 2) two separate developmental ages, and 3) examining, as exogenous stresses, responses to hypercapnia and asphyxia in wakefulness and sleep with and without afferent input from the carotid body.