Regulation of sleep-wake timing: Circadian rhythms and bistability of sleep-wake states.

摘要

Sleep is strongly modulated by circadian, homeostatic, and other influences, but little is known about how these factors influence sleep timing. This thesis examined several aspects of sleep timing by studying pathways linked with the ventrolateral preoptic nucleus (VLPO), which has been recently found to promote sleep by inhibiting many of the brain's wake-active monoaminergic arousal systems. Because little was known about afferents to the VLPO, our first aim broadly surveyed afferents to the VLPO using anatomic tracers. Results showed heavy inputs from widespread cortical, hypothalamic, limbic, and brainstem regions. VLPO neurons also received heavy inputs from their own monoaminergic targets, suggesting strong reciprocal connections between sleep- and wake-active systems. Our second aim examined pathways regulating the circadian rhythm of sleep. VLPO neurons receive only sparse inputs from the suprachiasmatic nucleus (SCN), the brain's circadian pacemaker, but we identified a major input from the dorsomedial hypothalamic nucleus (DMH), which receives inputs from the SCN. We found that cell-specific ibotenic acid lesions of the DMH reduced the day-night variation of sleep-wake behavior by 78–89%, with similar reductions of feeding, locomotor activity, and serum corticosteroid rhythms. We also found that the DMH may influence sleep via a mainly GABAergic projection to the VLPO, and a mainly glutamatergic projection to the wake-promoting lateral hypothalamic area, including orexin neurons. Our thud aim examined a neural network model of the reciprocal interactions between sleep- and wake-promoting neurons. Simulations of this circuit exhibited bistable behaviors similar to those observed experimentally, and correctly predicted that lesions of sleep- or wake-promoting neurons would increase the frequency of sleep-wake transitions. Our model also predicted the mathematical distribution of transient arousals during sleep, which have not been accounted for by previous sleep models. Overall, the circadian and stability mechanisms identified in this thesis have implications for understanding the sleep disorder narcolepsy, in which disruptions are seen in both the circadian timing and stability of sleep-wake states.