The important findings that a substantial subset of SIDS infants have decreases in serotonin receptor binding the ventral medulla form the basis for the hypothesis that abnormalities in the 'medullary 5-HT system' play an important rote in SIDS. Neurons in this region participate in widespread autonomic functions including cardiorespiratory control, thermoregutation, and based on recent new information from our laboratory, sleep. The overall aim of this proposal is to investigate the roles of phenotypically specific neurons in the medullary 5-HT system on sleep homeostasis, responses to a thermal stress, and on cardiorespiratory variability. Our strategy will be to use novel neurochemicals to locally inhibit or destroy serotonergic neurons and/or neurons expressing the 5-HT(1A), NK1, or m1 muscarinic receptor in chronically instrumented piglets. 8-OH DPAT will be used to selectively activate 5-HT(1A) autoreceptors on 5-HT neurons, and 5,7-DHT or the neurotoxin saporin conjugated to an antibody to the serotonin transporter protein (SERT-SAP) will be used to selectively destroy serotonergic neurons. Analogous methods will be usedto inhibit or destroy neurons expressing the NK1 or m1 muscarinic receptor with SP-SAP or a powerful toxin obtained from the venom of the green mamba highly selective for m1 muscarinic receptors (m1-toxin1). We will evaluate the effects of these specific 'lesions' on sleep architecture in piglets using EEG wavelet analysis and behavioral observations during short (6 hr) plethysmograph recordings, and long (12-24 hr) recordings in their natural habitat (with the sow and siblings) using telemetry. We will also evaluate responses to thermal stresses focusing on shivering and non-shivering thermogenesis, skin blood flow, and hyperpnea. Finally, we will use the sensitive techniques of fractal analysis to evaluate the complexity of cardiorespiratory variability, the decrease in which is associated with decreased ability of a control system to respond to a perturbation. Indeed, infants who subsequently die of SIDS have decreases in heart rate variability. Lesions will be made in the midline and lateral columns and all areas simultaneously to test the hypothesis that neurons are organized in a functionally specific manner. We hypothesize that the medullary 5-HT system is a major site for the integration of cardiorespiratory, thermoregulatory, and sleep and arousal mechanisms, and that abnormalities in this region could produce local or widespread effects that might contribute to sudden death.
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