02 Saper 05-11

1257 In 1916, Baron Constantin von Economo, a Viennese neurologist, began to see patients with a new type of encephalitis that specifically attacked regions of the brain that regulate sleep and wakefulness. This disorder, which was eventually called encephalitis lethargica or von Economo’s sleeping sickness, swept through Europe and North America during the second decade of the twentieth century; by the end of the following decade it had apparently disappeared, as only sporadic and unconvincing reports have appeared since. Although the virus that caused it was never identified, von Economo was able to identify the areas of the brain in which lesions caused specific alterations of wake–sleep regulation (Fig. 1). Only during the past decade has the accuracy of his observations come to be appreciated, as key components of the wake–sleep-regulatory system were found to reside at the sites that von Economo first identified. In this review, we cover recent advances in understanding the brain circuitry that regulates sleep and produces wakefulness, including cell groups in the brainstem, hypothalamus and basal forebrain (BF) that are crucial for arousing the cerebral cortex and thalamus. These neurons are inhibited during sleep by a system of -aminobutyric acid (GABA)-containing neurons, in which the ventrolateral preoptic nucleus (VLPO) seems to have a key role. Mutual inhibition between the arousaland sleep-producing circuitry results in switching properties that define discrete wake and sleep states, with sharp transitions between them. We examine how this switch is stabilized by orexin neurons in the lateral hypothalamus (LHA), and why loss of these neurons results in narcolepsy. We also explore how basic drives affect this system, including the homeostatic need to sleep that accumulates as a function of prolonged wakefulness, the circadian drive that moulds the daily cycles of sleep–wakefulness, and allostatic influences that adapt sleep and wakefulness to external behavioural events. Interactions with this circuitry might explain the effects of a range of drugs on sleep and wakefulness.