Trends in Neurosciences
Volume 24, Issue 12, 1 December 2001, Pages 726-731
Journal home page for Trends in Neurosciences

Review
The sleep switch: hypothalamic control of sleep and wakefulness

https://doi.org/10.1016/S0166-2236(00)02002-6Get rights and content

Abstract

More than 70 years ago, von Economo predicted a wake-promoting area in the posterior hypothalamus and a sleep-promoting region in the preoptic area. Recent studies have dramatically confirmed these predictions. The ventrolateral preoptic nucleus contains GABAergic and galaninergic neurons that are active during sleep and are necessary for normal sleep. The posterior lateral hypothalamus contains orexin/hypocretin neurons that are crucial for maintaining normal wakefulness. A model is proposed in which wake- and sleep-promoting neurons inhibit each other, which results in stable wakefulness and sleep. Disruption of wake- or sleep-promoting pathways results in behavioral state instability.

Section snippets

The cholinergic and monoaminergic substrates of arousal

In the years after World War II, Moruzzi, Magoun and many others contributed to identifying an ascending pathway that regulates the level of forebrain wakefulness 12. Transection of the brainstem at the midpons or below did not reduce arousal, whereas slightly more rostral transections at a midcollicular level caused an acute loss of wakefulness. The wake-promoting outflow from this crucial slab of tissue at the rostral pontine–caudal midbrain interface was traced by anatomical and

The ‘off’ switch

Because the firing of monoaminergic neurons is state dependent, understanding the sources of inputs to these cell groups provides a window into the mechanisms that regulate wakefulness. Sherin and colleagues have found two major inputs to the TMN core: (1) a population of diffusely distributed neurons in the lateral hypothalamic area; and (2) a dense cluster of neurons in the ventrolateral preoptic nucleus (VLPO cluster), surrounded medially and dorsally by a more diffuse extension from the

Is the VLPO necessary for sleep?

To determine whether the VLPO neurons are necessary for producing sleep, Lu and colleagues produced small excitotoxic lesions in the lateral preoptic area by microinjecting ibotenic acid 41. Although previous studies have demonstrated insomnia after injury to this region, these lesions injured fiber pathways 3, 5 or involved much of the preoptic area beyond the VLPO (42, 43). In order to analyze the lesions, the numbers of remaining Fos-immunoreactive cell bodies in the VLPO cluster and the

The flip–flop and bistability

The relationship between the VLPO and the major monoamine groups appears to be reciprocal. The VLPO is innervated by histaminergic axons from the TMN, noradrenergic terminals from the locus coeruleus and serotoninergic inputs from the midbrain raphé nuclei 45. Recordings from individual VLPO neurons in hypothalamic slices show that they are inhibited by noradrenaline and by 5-HT (Ref. 46). No responses to histamine were recorded, but TMN neurons also contain GABA and galanin, which might

Stabilizing the flip–flop

A similar deficit on the waking side of the mutually inhibitory flip–flop circuit might produce abrupt and unstable fluctuations in behavioral state in the disorder known as narcolepsy. Individuals with narcolepsy experience frequent and unwanted transitions into sleep during wakefulness, and they tend to awaken more frequently from sleep as well. When placed in a quiet environment, they fall asleep and transition into REM sleep far more rapidly than unaffected individuals. At times, they

Concluding remarks

Advances over the past five years have largely borne out the remarkable predictions of von Economo, which were made over 70 years ago on the basis of clinical observations. The occurrence of insomnia in individuals with lesions of the preoptic area and basal forebrain was almost certainly due to the involvement of the VLPO in these cases. The hypersomnolent individuals clearly had lesions of the ascending arousal pathways at the midbrain–diencephalic junction. And von Economo's prediction that

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