Based on observations made in brainstem tissue of SIDS cases we hypothesize that the pathogenesis of SIDS involves abnormalities in what we now call the 'medullary serotonergic system'. In this project we define in newborn piglets the neuroehemical and receptor anatomy of the neurons in the medullary serotonergic system, we specifically disrupt them focally or widely, and we observe the resultant effects on an army of homeostatic processes. These include the ventilatory responses to increased CO2 and decreased O2, upper airway reflexes, and blood pressure effects on breathing. We use an unanesthetized newborn piglet model in which we can easily test this array of homeostatic processes in both wakefulness and sleep. Initially we inhibit serotoncrgic neurons by microdialysis of an agonist for the 5-HT(1A) autorceeptor or kill them by injection of 5, 7 DHT or a conjugate of anantibody for the serotonin transport protein (SERT) and the cell toxin saporin (SAP). We will also inhibit and kill neurons within the medullary serotonergic system that express the NK1 or muscarinic M1 subtype receptors. For neurons with NK1 receptors we use an NK1 antagonist or substance P-SAP. For neurons with M1 receptors we use telenzepine or the m1-toxin1 (a highly specific long acting M1 receptor antagonist). These experiments will involve focal application at various sites within three rostral-to-caudal colulumns that define the medullary serotonergic system or widely at 'all' sites simultaneously. With focal application we ask if each homeostatic process can be localized to a specific site within the medullary serotonergic system. With wide application we ask if these homeostatic processes utilize neurons distributed at many locations. Serotonergic neurons within the meduliary serotonergic system can be further classified by peptides that are co-localized within them. Thyrotropin releasing hormone (TRH) and substance P (SP) are two such that are of particular interest in that they have known strong effects on breathing and blood pressure. We will microdialyze T3 in the medullary raphe, which will bind to nuclear beta2 thyroid receptors and inhibit TRH production and release allowing us to examine the role of endogenous TRH in the function of our array of homeostatic processes. Overall, the goal of this project is to see if a induced focal or widely distributed abnormality in the medullary semtonergic system couid affect function in our array of homeostatic processes such as to contribute to sudden death.
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