The proposed studies will evaluate elements of a hypothesis in which mammalian slow wave sleep (SWS) is understood as a thermoregulatory process that is controlled primarily by activity of hypothalamic thermoregulatory neurons. The existence of hypnogenic mechanisms in the preoptic area-anterior hypothalamus (POAH) and adjacent basal forebrain has been supported by neuronal unit recording, stimulation, and lesion methodologies. Other evidence shows that the hypnogenic and thermoregulatory functions of the POAH are closely integrated and regulated by a functional temperature 'set point"""""""". We hypothesize that the POAH hypnogenic output is controlled by a subset of thermosensitive neurons which induce changes in EEG, hormonal, autonomic, and motor activity as an integrated thermoregulatory response, producing heat loss and reduced metabolic rate. These neurons are hypothesized to encode the duration of prior waking and to integrate circadian and homeostatic controls of sleep through dynamic changes in thermosensitivity. With neuronal unit recording techniques in behaving animals, POAH thermosensitive neurons will be identified and retested sequentially in conjunction with EEG-sleep variables. Proposed studies will evaluate a series of predictions concerning a subset of putative hypnogenic neurons, based on a quantitative thermoregulatory model. We predict that warm-sensitivity will be 1) increased with extended time awake, that is, sleep deprivation, 2) decreased with extended time asleep, 3) increased by sustained hypothalamic warming, 4) decreased with sustained hypothalamic cooling, 5) correlated with sleep depth as determined by EEG spectral analysis, 6) and increased by IL-1 (in combination with indomethacin) and PGD2. Hypnogenic cold-sensitive neurons would exhibit opposite changes. Critical thermosensitive neurons would have unique connections to basal forebrain and brainstem systems. In addition, sustained hypothalamic warming and cooling will increase and decrease, respectively subsequent sleep. These studies would provide a model for classification of thermosensitive neuronal subtypes described previously. Development of a hypothesis that SWS is a thermoregulatory process would provide a basis for analysis of sleep homeostasis, analogous to isolating critical feedback signals for other homeostatic systems such as blood gases in respiratory physiology. This approach would be applicable to neural and behavioral studies of sleep in birds and mammals, including man, and would have significance for a understanding a range of disorders characterized by SWS loss, including depression and Narcolepsy, as well as effects of sleep deprivation.
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